Abstract
The past few decades have seen an increased emphasis on the involvement of the mitochondrial-associated membrane (MAM) in various neurodegenerative diseases, particularly in Parkinson’s disease (PD) and Alzheimer’s disease (AD). In PD, alterations in mitochondria, endoplasmic reticulum (ER), and MAM functions affect the secretion and metabolism of proteins, causing an imbalance in calcium homeostasis and oxidative stress. These changes lead to alterations in the translocation of the MAM components, such as IP3R, VDAC, and MFN1 and 2, and consequently disrupt calcium homeostasis and cause misfolded proteins with impaired autophagy, distorted mitochondrial dynamics, and cell death. Various reports indicate the detrimental involvement of the brain renin–angiotensin system (RAS) in oxidative stress, neuroinflammation, and apoptosis in various neurodegenerative diseases. In this review, we attempted to update the reports (using various search engines, such as PubMed, SCOPUS, Elsevier, and Springer Nature) demonstrating the pathogenic interactions between the various proteins present in mitochondria, ER, and MAM with respect to Parkinson’s disease. We also made an attempt to speculate the possible involvement of RAS and its components, i.e., AT1 and AT2 receptors, angiotensinogen, in this crosstalk and PD pathology. The review also collates and provides updated information on the role of MAM in calcium signaling, oxidative stress, neuroinflammation, and apoptosis in PD.
Highlights
We have summarized the evidence on the participation of the mitochondria and endoplasmic reticulum (ER) in Parkinson’s disease (PD) pathology, and the crosstalk between these organelles at the mitochondrial-associated membrane (MAM)
Any mitochondria, leading to mitochondrial dysfunction, followed by loss of dopaminergic neurons [56]. Another major evidence by Chan et al reported that juvenile dopaminergic neurons in the substantia nigra pars compacta (SNpc) depend on the L-type Ca (v) 13 Ca2+ channels for rhythmic pacemaking, which provides a sustained increase in cytosolic Ca2+ concentration in the cells
MAM provides a platform for crosstalk between the ER and mitochondria, allowing rapid exchange of biological molecules to maintain cellular homeostasis
Summary
Parkinson’s disease (PD) was first described in 1817 by Dr James Parkinson, a British physician, as “shaking palsy”. Accumulation of misfolded proteins is reported as one of the key pathogenic factors that aggravates PD. Several investigations on PD suggest that oxidative stress and bioenergy crisis impair neuronal clearance of misfolded proteins, α-synuclein (α-Syn), leading to neurodegeneration [6,7,8]. Irregular protein conformation of α-Syn, along with intracellular accumulation of Lewy body (LB) and other proteins, such as Aβ and phosphorylated tau (p-Tau), in SNpc dopamine neurons, are frequently reported in the PD post-mortem brains [9]. RAS participates in regulating the cerebral blood flow; its overactivation is reported to have a pathogenic link in neurological disorders, such as PD, Alzheimer’s disease (AD), transient cerebral ischemia, and depression, and in memory consolidation. Dopaminergic neurons in the brain possess local RAS components, viz., angiotensin II (Ang II) type 1 and type 2 receptors [13]. Mitochondria and ER play a crucial role in oxidative stress, neuroinflammation, and apoptosis, and so does RAS; we made an attempt to link the possible interactions between RAS–mitochondria–ER at MAM and its impact in PD
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