Translational Neurodegeneration最新文献

{"title":"The relation of synaptic biomarkers with Aβ, tau, glial activation, and neurodegeneration in Alzheimer's disease.","authors":"Yi-Ting Wang, Nicholas J Ashton, Stijn Servaes, Johanna Nilsson, Marcel S Woo, Tharick A Pascoal, Cécile Tissot, Nesrine Rahmouni, Joseph Therriault, Firoza Lussier, Mira Chamoun, Serge Gauthier, Ann Brinkmalm, Henrik Zetterberg, Kaj Blennow, Pedro Rosa-Neto, Andréa L Benedet","doi":"10.1186/s40035-024-00420-1","DOIUrl":"10.1186/s40035-024-00420-1","url":null,"abstract":"","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":"27"},"PeriodicalIF":12.6,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11131272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141158019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CSF biomarkers of reactive glial cells are associated with blood-brain barrier leakage and white matter lesions.","authors":"Linbin Dai, Xinyi Lv, Zhaozhao Cheng, Yan Wu, Xianliang Chai, Jiong Shi, Yong Shen, Qiong Wang, Feng Gao","doi":"10.1186/s40035-024-00422-z","DOIUrl":"10.1186/s40035-024-00422-z","url":null,"abstract":"","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":"26"},"PeriodicalIF":12.6,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11112808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141088765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Considerations for biomarker strategies in clinical trials investigating tau-targeting therapeutics for Alzheimer's disease.","authors":"Lewis K Penny, Richard Lofthouse, Mohammad Arastoo, Andy Porter, Soumya Palliyil, Charles R Harrington, Claude M Wischik","doi":"10.1186/s40035-024-00417-w","DOIUrl":"10.1186/s40035-024-00417-w","url":null,"abstract":"<p><p>The use of biomarker-led clinical trial designs has been transformative for investigating amyloid-targeting therapies for Alzheimer's disease (AD). The designs have ensured the correct selection of patients on these trials, supported target engagement and have been used to support claims of disease modification and clinical efficacy. Ultimately, this has recently led to approval of disease-modifying, amyloid-targeting therapies for AD; something that should be noted for clinical trials investigating tau-targeting therapies for AD. There is a clear overlap of the purpose of biomarker use at each stage of clinical development between amyloid-targeting and tau-targeting clinical trials. However, there are differences within the potential context of use and interpretation for some biomarkers in particular measurements of amyloid and utility of soluble, phosphorylated tau biomarkers. Given the complexities of tau in health and disease, it is paramount that therapies target disease-relevant tau and, in parallel, appropriate assays of target engagement are developed. Tau positron emission tomography, fluid biomarkers reflecting tau pathology and downstream measures of neurodegeneration will be important both for participant recruitment and for monitoring disease-modification in tau-targeting clinical trials. Bespoke design of biomarker strategies and interpretations for different modalities and tau-based targets should also be considered.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":"25"},"PeriodicalIF":12.6,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11107038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141076776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Agomirs upregulating carboxypeptidase E expression rescue hippocampal neurogenesis and memory deficits in Alzheimer’s disease","authors":"Dongfang Jiang, Hongmei Liu, Tingting Li, Song Zhao, Keyan Yang, Fuwen Yao, Bo Zhou, Haiping Feng, Sijia Wang, Jiaqi Shen, Jinglan Tang, Yu-Xin Zhang, Yun Wang, Caixia Guo, Tie-Shan Tang","doi":"10.1186/s40035-024-00414-z","DOIUrl":"https://doi.org/10.1186/s40035-024-00414-z","url":null,"abstract":"Adult neurogenesis occurs in the subventricular zone (SVZ) and the subgranular zone of the dentate gyrus in the hippocampus. The neuronal stem cells in these two neurogenic niches respond differently to various physiological and pathological stimuli. Recently, we have found that the decrement of carboxypeptidase E (CPE) with aging impairs the maturation of brain-derived neurotrophic factor (BDNF) and neurogenesis in the SVZ. However, it remains unknown whether these events occur in the hippocampus, and what the role of CPE is in the adult hippocampal neurogenesis in the context of Alzheimer’s disease (AD). In vivo screening was performed to search for miRNA mimics capable of upregulating CPE expression and promoting neurogenesis in both neurogenic niches. Among these, two agomirs were further assessed for their effects on hippocampal neurogenesis in the context of AD. We also explored whether these two agomirs could ameliorate behavioral symptoms and AD pathology in mice, using direct intracerebroventricular injection or by non-invasive intranasal instillation. Restoration of CPE expression in the hippocampus improved BDNF maturation and boosted adult hippocampal neurogenesis. By screening the miRNA mimics targeting the 5’UTR region of Cpe gene, we developed two agomirs that were capable of upregulating CPE expression. The two agomirs significantly rescued adult neurogenesis and cognition, showing multiple beneficial effects against the AD-associated pathologies in APP/PS1 mice. Of note, noninvasive approach via intranasal delivery of these agomirs improved the behavioral and neurocognitive functions of APP/PS1 mice. CPE may regulate adult hippocampal neurogenesis via the CPE–BDNF–TrkB signaling pathway. This study supports the prospect of developing miRNA agomirs targeting CPE as biopharmaceuticals to counteract aging- and disease-related neurological decline in human brains.","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"26 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140800362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Focusing on mitochondria in the brain: from biology to therapeutics","authors":"Nanshan Song, Shuyuan Mei, Xiangxu Wang, Gang Hu, Ming Lu","doi":"10.1186/s40035-024-00409-w","DOIUrl":"https://doi.org/10.1186/s40035-024-00409-w","url":null,"abstract":"Mitochondria have multiple functions such as supplying energy, regulating the redox status, and producing proteins encoded by an independent genome. They are closely related to the physiology and pathology of many organs and tissues, among which the brain is particularly prominent. The brain demands 20% of the resting metabolic rate and holds highly active mitochondrial activities. Considerable research shows that mitochondria are closely related to brain function, while mitochondrial defects induce or exacerbate pathology in the brain. In this review, we provide comprehensive research advances of mitochondrial biology involved in brain functions, as well as the mitochondria-dependent cellular events in brain physiology and pathology. Furthermore, various perspectives are explored to better identify the mitochondrial roles in neurological diseases and the neurophenotypes of mitochondrial diseases. Finally, mitochondrial therapies are discussed. Mitochondrial-targeting therapeutics are showing great potentials in the treatment of brain diseases.","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 32 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140608669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of the brain renin-angiotensin system in Parkinson´s disease","authors":"Jose Luis Labandeira-Garcia, Carmen M. Labandeira, Maria J. Guerra, Ana I. Rodriguez-Perez","doi":"10.1186/s40035-024-00410-3","DOIUrl":"https://doi.org/10.1186/s40035-024-00410-3","url":null,"abstract":"The renin-angiotensin system (RAS) was classically considered a circulating hormonal system that regulates blood pressure. However, different tissues and organs, including the brain, have a local paracrine RAS. Mutual regulation between the dopaminergic system and RAS has been observed in several tissues. Dysregulation of these interactions leads to renal and cardiovascular diseases, as well as progression of dopaminergic neuron degeneration in a major brain center of dopamine/angiotensin interaction such as the nigrostriatal system. A decrease in the dopaminergic function induces upregulation of the angiotensin type-1 (AT1) receptor activity, leading to recovery of dopamine levels. However, AT1 receptor overactivity in dopaminergic neurons and microglial cells upregulates the cellular NADPH-oxidase-superoxide axis and Ca2+ release, which mediate several key events in oxidative stress, neuroinflammation, and α-synuclein aggregation, involved in Parkinson's disease (PD) pathogenesis. An intraneuronal antioxidative/anti-inflammatory RAS counteracts the effects of the pro-oxidative AT1 receptor overactivity. Consistent with this, an imbalance in RAS activity towards the pro-oxidative/pro-inflammatory AT1 receptor axis has been observed in the substantia nigra and striatum of several animal models of high vulnerability to dopaminergic degeneration. Interestingly, autoantibodies against angiotensin-converting enzyme 2 and AT1 receptors are increased in PD models and PD patients and contribute to blood–brain barrier (BBB) dysregulation and nigrostriatal pro-inflammatory RAS upregulation. Therapeutic strategies addressed to the modulation of brain RAS, by AT1 receptor blockers (ARBs) and/or activation of the antioxidative axis (AT2, Mas receptors), may be neuroprotective for individuals with a high risk of developing PD or in prodromal stages of PD to reduce progression of the disease.","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"58 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRISPR base editing-mediated correction of a tau mutation rescues cognitive decline in a mouse model of tauopathy","authors":"Min Sung Gee, Eunji Kwon, Myeong-Hoon Song, Seung Ho Jeon, Namkwon Kim, Jong Kil Lee, Taeyoung Koo","doi":"10.1186/s40035-024-00415-y","DOIUrl":"https://doi.org/10.1186/s40035-024-00415-y","url":null,"abstract":"&lt;p&gt;The microtubule-binding protein tau is encoded by &lt;i&gt;MAPT&lt;/i&gt;, located on chromosome 17. Mutations in this gene have been implicated in frontotemporal dementia [1]. Down-regulation of endogenous tau with antisense oligonucleotides (ASOs) specific for human tau or zinc-finger protein transcription factors has been explored in preclinical models of tauopathy [2, 3]. Of particular note, the effects of tau ASOs on mild Alzheimer’s disease are now under assessment in a clinical trial [4]. In addition, CRISPR-mediated gene knockout has been used to regulate the expression of &lt;i&gt;APP&lt;/i&gt; or &lt;i&gt;BACE1&lt;/i&gt; to ameliorate amyloid β and tau pathologies [5, 6]. However, therapeutic approaches to correcting &lt;i&gt;MAPT&lt;/i&gt; mutations that cause tau aggregation in animal models of tauopathy have not yet been studied.&lt;/p&gt;&lt;p&gt;CRISPR RNA-guided base editors have been recently used for targeted base mutagenesis in the genome and have become a promising approach for the treatment of neurological disorders [6]. The recently developed adenine base editor, NG-ABE8e, which is a fusion of SpCas9-NG derived from &lt;i&gt;Streptococcus pyogenes&lt;/i&gt; and an evolved &lt;i&gt;E. coli&lt;/i&gt; TadA monomer that is used in combination with a single-guide RNA (sgRNA), generates A-to-G conversions in the spacer upstream of an NG protospacer adjacent motif (PAM). NG-ABE8e has demonstrated an efficient genome editing ability, targeting a window spanning positions 4–11 in the protospacer [7].&lt;/p&gt;&lt;p&gt;In this study, we examined whether NG-ABE8e could be used to correct a pathogenic &lt;i&gt;MAPT&lt;/i&gt; mutation and thereby reduce tauopathy and cognitive symptoms in the PS19 transgenic mouse model expressing human &lt;i&gt;MAPT-&lt;/i&gt;P301S. To evaluate the ability of NG-ABE8e to correct the &lt;i&gt;MAPT&lt;/i&gt;-P301S mutant allele to the wild-type (WT) sequence, we designed sgRNAs targeting the &lt;i&gt;MAPT&lt;/i&gt;-P301S mutation. The sgRNAs were designed to hybridize with a 19-nt target sequence upstream of a TG PAM to replace the A, located 11 nt distal from the 5′-end of protospacer (Fig. 1a and Additional file 1: Table S1). Next, we evaluated the activity of the sgRNA by using targeted deep sequencing to measure adenine base editing frequencies after transfection of plasmids encoding NG-ABE8e and the sgRNAs into HEK293T cells harboring the P301S mutation (293T-P301S) (Additional file 1: Fig. S1a). The desired A-to-G substitution induced by NG-ABE8e corrected the mutant allele to the WT &lt;i&gt;MAPT&lt;/i&gt; sequence, with an observed editing frequency of 16.6% ± 0.8% in the cells (Additional file 1: Fig. S1b). Bystander editing or indels were not detectable in the protospacer. We also designed sgRNAs to target exon 1 in the mouse &lt;i&gt;Rosa26&lt;/i&gt; gene as an internal control (Additional file 1: Fig. S1c and Table S1). Treatment of NIH3T3 cells with NG-ABE8e and a &lt;i&gt;Rosa26&lt;/i&gt;-targeting sgRNA resulted in a base-editing frequency of 29.4% ± 1.3% (Additional file 1: Fig. S1d).&lt;/p&gt;&lt;figure&gt;&lt;figcaption&gt;&lt;b data-test=\"figure-caption-text\"&gt;Fig. 1&lt;/b&gt;&lt;/figcaptio","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"12 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stathmin 2 is a potential treatment target for TDP-43 proteinopathy in amyotrophic lateral sclerosis","authors":"Yunqing Liu, Dejun Yan, Lin Yang, Xian Chen, Chun Hu, Meilan Chen","doi":"10.1186/s40035-024-00413-0","DOIUrl":"https://doi.org/10.1186/s40035-024-00413-0","url":null,"abstract":"&lt;p&gt;Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons (MNs), resulting in progressive disability and mortality with a rapid course. Current approaches such as multidisciplinary care, disease-modifying therapies, pulmonary intervention, and dietary and nutritional intervention can only slow ALS progression [1]. It is imperative to dissect the underlying mechanisms and explore novel treatment targets.&lt;/p&gt;&lt;p&gt;Trans-reactive DNA binding protein 43 KD (TDP-43) is a main component of abnormal cytoplasmic protein deposits observed in ~ 97% of ALS patients, and its presence is considered a pathological hallmark of ALS regardless of the disease onset. Physiologically, TDP-43 is a multifunctional protein that predominantly localizes to the nucleus, where it binds to GU-rich sequences for selective splicing. It also shuttles to the cytoplasm to generate ribonucleoprotein transport/stress granules and control translation. However, abnormal modifications of TDP-43 reduce its functional level in the nucleus and promotes the formation of cytoplasmic inclusions in MNs, inducing neurotoxic effects known as TDP-43 proteinopathy.&lt;/p&gt;&lt;p&gt;Initial efforts were dedicated to analyzing the binding sites of TDP-43 in mouse and human brains, showing that TDP-43 could target approximately 1000 mRNAs, a large portion being glial RNAs, providing limited insights into neuronal targets. The following study established a method for inducing human embryonic stem cells to differentiate into human MNs (hMNs), providing a more reliable model for investigating disease stimuli and therapeutic strategies [2]. With induced hMNs, Klim et al. [3] revealed that the expression of stathmin-2 (STMN2) was significantly reduced upon TDP-43 depletion. Similar results have been observed in patient-derived MNs and postmortem patient spinal cords harboring TDP-43 mislocalization [4]. Mechanistically, functional TDP-43 binds directly to &lt;i&gt;STMN2&lt;/i&gt; pre-mRNA to maintain normal splicing. Pathological TDP-43 drives premature polyadenylation and cryptic splicing in the first intron of &lt;i&gt;STMN2&lt;/i&gt; pre-mRNA, leading to the production of a nonfunctional mRNA [4]. Reduction of TDP-43 or STMN2 in iPSC-derived MNs inhibited axonal regeneration after induced damage. Notably, restoration/stabilization of STMN2 rescued neurite outgrowth and axon regeneration in the absence of TDP-43 [3, 4].&lt;/p&gt;&lt;p&gt;STMN2 belongs to the conserved Stathmin family. It can depolymerize microtubules via unclear mechanisms and is specifically expressed in the nervous system for axonal development and maintenance (see details in [5]). A moderate level of STMN2 stimulates neurite outgrowth by modulating microtubule dynamics, whereas excessive or reduced levels of STMN2 cause growth cone collapse or suppress neurite outgrowth in neurons. In cultured sensory neurons from dorsal root ganglion (DRG) subjected to axotomy, Stmn2 was elevated in regenerating growth cones. Downr","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"47 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathophysiological subtypes of mild cognitive impairment due to Alzheimer’s disease identified by CSF proteomics","authors":"Daniela Moutinho, Vera M. Mendes, Alessandro Caula, Sara C. Madeira, Inês Baldeiras, Manuela Guerreiro, Sandra Cardoso, Johan Gobom, Henrik Zetterberg, Isabel Santana, Alexandre De Mendonça, Helena Aidos, Bruno Manadas","doi":"10.1186/s40035-024-00412-1","DOIUrl":"https://doi.org/10.1186/s40035-024-00412-1","url":null,"abstract":"&lt;p&gt;The number of patients with Alzheimer's disease (AD) is increasing worldwide due to extended life expectancy, with AD being the most common cause of dementia. AD pathological hallmarks consist of brain depositions of aggregated amyloid beta (Aβ) into neuritic plaques and neurofibrillary tangles of hyperphosphorylated tau, leading to synaptic dysfunction and neuronal loss [1]. Proteomic studies of cerebrospinal fluid (CSF) have shown that several biological processes are dysregulated in AD, such as the innate immune system, inflammatory response, hemostasis, lipid processing, oxidative stress response and synaptic functioning [2]. Some of these alterations may already be present at the early stages of the disorder. Remarkably, a recent study identified three biological AD subtypes based on the CSF proteome of two independent AD cohorts as having hyperplasticity, innate immune activation and blood–brain barrier dysfunction profiles, respectively [3]. Proteomic studies have usually compared AD patients with healthy control subjects; however, patients with AD, even at initial stages corresponding to mild cognitive impairment (MCI), show modifications in lifestyle, changes in diet, weight loss, and presence of comorbidities and drug treatments. As a consequence, metabolic, inflammatory and immune changes might occur that could potentially translate into an altered proteome. The existence of different AD subtypes through CSF proteomics, coupled with a deep understanding of the underlying pathological mechanisms in early stages, holds significant implications for comprehending the disease. It also has profound consequences for the development of disease-modifying treatments, which may need to be tailored to benefit specific subtypes of the disease, eventually being ineffective or even detrimental in others.&lt;/p&gt;&lt;p&gt;The present work (Additional file 1: Fig. S1) represents original features in relation to previous studies, since we (1) focused on the initial phases of AD, that is, patients with MCI within the Cognitive Complaints Cohort (CCC) [4]; (2) recruited patients with MCI who exhibited amyloid and neuronal injury biomarkers indicative of a high likelihood of AD (MCI&lt;sub&gt;AD&lt;/sub&gt;; &lt;i&gt;n&lt;/i&gt; = 45; adapted from the National Institute on Aging—Alzheimer’s Association workgroups [5]); (3) selected a control group of MCI patients without any biomarkers of Aβ deposition or neuronal injury (MCI&lt;sub&gt;Other&lt;/sub&gt;; &lt;i&gt;n&lt;/i&gt; = 23), in order to control for nonspecific changes that might influence the CSF proteome in patients with MCI; and (4) applied the same methodology to MCI patients with (&lt;i&gt;n&lt;/i&gt; = 92) and without (&lt;i&gt;n&lt;/i&gt; = 102) AD pathology from the European Medical Information Framework for Alzheimer’s Disease (EMIF-AD) cohort for further validation (Fig. 1a and Additional file 2: Tables S1).&lt;/p&gt;&lt;figure&gt;&lt;figcaption&gt;&lt;b data-test=\"figure-caption-text\"&gt;Fig. 1&lt;/b&gt;&lt;/figcaption&gt;&lt;picture&gt;&lt;source srcset=\"//media.springernature.com/lw685/springer-static/image/ar","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"121 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dietary fasting and time-restricted eating in Huntington's disease: therapeutic potential and underlying mechanisms.","authors":"Russell G Wells, Lee E Neilson, Andrew W McHill, Amie L Hiller","doi":"10.1186/s40035-024-00406-z","DOIUrl":"10.1186/s40035-024-00406-z","url":null,"abstract":"<p><p>Huntington's disease (HD) is a devastating neurodegenerative disorder caused by aggregation of the mutant huntingtin (mHTT) protein, resulting from a CAG repeat expansion in the huntingtin gene HTT. HD is characterized by a variety of debilitating symptoms including involuntary movements, cognitive impairment, and psychiatric disturbances. Despite considerable efforts, effective disease-modifying treatments for HD remain elusive, necessitating exploration of novel therapeutic approaches, including lifestyle modifications that could delay symptom onset and disease progression. Recent studies suggest that time-restricted eating (TRE), a form of intermittent fasting involving daily caloric intake within a limited time window, may hold promise in the treatment of neurodegenerative diseases, including HD. TRE has been shown to improve mitochondrial function, upregulate autophagy, reduce oxidative stress, regulate the sleep-wake cycle, and enhance cognitive function. In this review, we explore the potential therapeutic role of TRE in HD, focusing on its underlying physiological mechanisms. We discuss how TRE might enhance the clearance of mHTT, recover striatal brain-derived neurotrophic factor levels, improve mitochondrial function and stress-response pathways, and synchronize circadian rhythm activity. Understanding these mechanisms is critical for the development of targeted lifestyle interventions to mitigate HD pathology and improve patient outcomes. While the potential benefits of TRE in HD animal models are encouraging, future comprehensive clinical trials will be necessary to evaluate its safety, feasibility, and efficacy in persons with HD.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":"17"},"PeriodicalIF":12.7,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10986006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140336913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}