Calpain Mediated Neurodegeneration in Parkinson’s disease

Abstract

Parkinson’s disease (PD), a neurodegenerative movement disorder, is clinically manifested by disturbances in motor functions and non-motor symptoms, caused by progressive degeneration of nigrostriatal dopaminergic neurons and neurons in selected areas of the central and peripheral nervous system. The multifaceted pathogenesis of PD is associated with sustained mitochondrial dysfunction, oxidative stress, aberrant Са²⁺ homeostasis, which contribute to the activation of Са²⁺-dependent protease calpain. Calpain plays role in neuronal signaling mechanisms, ensuring the normal course of intracellular neurochemical and neurophysiological processes. In neuropathological conditions, elevation of intracellular Ca²⁺ and calpain activation, downregulation of endogenous and/or absence of exogenous pharmacological inhibitors of calpain, instigate calpain-mediated activation of apoptotic pathways, leading to degeneration and loss of selectively vulnerable nigrostriatal dopaminergic neurons in the brain. We have shown that at experimental (in vivo, in vitro) and human (postmortem) PD dorsal neurons and ventral motoneurons of the spinal cord are also affected through the calpain-mediated mechanisms of neurodegeneration. Synthetic calpain inhibitors – calpeptin, SNJ1945, and SJA6017, exhibited neuroprotective effects in the brain and spinal cord (in vivo, in vitro), suggesting calpain as a prospective target molecule for pharmacological therapy in the brain and spinal cord at PD.