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Review
. 2024 Jun 13;25(12):6525.
doi: 10.3390/ijms25126525.

A-Syn(ful) MAM: A Fresh Perspective on a Converging Domain in Parkinson's Disease

Peter A Barbuti  1
Affiliations
Review

A-Syn(ful) MAM: A Fresh Perspective on a Converging Domain in Parkinson's Disease

Peter A Barbuti. Int J Mol Sci. .

Abstract

Parkinson's disease (PD) is a disease of an unknown origin. Despite that, decades of research have provided considerable evidence that alpha-synuclein (αSyn) is central to the pathogenesis of disease. Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are functional domains formed at contact sites between the ER and mitochondria, with a well-established function of MAMs being the control of lipid homeostasis within the cell. Additionally, there are numerous proteins localized or enriched at MAMs that have regulatory roles in several different molecular signaling pathways required for cellular homeostasis, such as autophagy and neuroinflammation. Alterations in several of these signaling pathways that are functionally associated with MAMs are found in PD. Taken together with studies that find αSyn localized at MAMs, this has implicated MAM (dys)function as a converging domain relevant to PD. This review will highlight the many functions of MAMs and provide an overview of the literature that finds αSyn, in addition to several other PD-related proteins, localized there. This review will also detail the direct interaction of αSyn and αSyn-interacting partners with specific MAM-resident proteins. In addition, recent studies exploring new methods to investigate MAMs will be discussed, along with some of the controversies regarding αSyn, including its several conformations and subcellular localizations. The goal of this review is to highlight and provide insight on a domain that is incompletely understood and, from a PD perspective, highlight those complex interactions that may hold the key to understanding the pathomechanisms underlying PD, which may lead to the targeted development of new therapeutic strategies.

Keywords: Parkinson’s disease (PD); alpha-synuclein (αSyn); mitochondrial-associated ER membranes (MAMs).

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
A schematic diagram containing some of the functions at the MAM domain, including relevant MAM proteins. Selected PARK proteins and PD-related proteins that have been found to localize to the MAM are shown and attributed to an associated function. These functions are loosely separated by dashed lines into six sub-sections: Autophagy, Apoptosis, Inflammation, Lipid metabolism, PtdSer synthesis, and Calcium homeostasis. Note that for each sub-section, αSyn is included, and some proteins or tethers have multiple roles or interactions other than those illustrated. The four established MAM tethers are designated by the white numbers 1–4 in the black circles: (1) VAPB-PTPIP51, (2) MFN2, (3) BAP31-FIS1, and (4) IP3R-GRP75-VDAC. Selected PARK or PD-relevant risk proteins found at the MAM in addition to αSyn include: VPS13, MIRO, Parkin, PINK1, 14-3-3, LRRK2, DJ-1, and GRP75/Mortalin. Abbreviations: VPS13: vacuolar protein sorting protein 13; ATG5: autophagy-related 5; STX17: Syntaxin 17; mTOR2: mechanistic target of rapamycin 2; MIRO: Mitochondrial Rho GTPase; PINK1: PTEN-induced putative kinase 1; VAPB: vesicle-associated membrane protein B; PTPIP51: protein tyrosine phosphatase-interacting protein-51; AMPK: 5′ AMP-activated protein kinase; MFN2: Mitofusin-2; BCL2: B-cell lymphoma 2; TOM20: translocase of the outer mitochondrial membrane complex subunit 20; PACS2: phosphofurin acidic cluster sorting protein 2; DRP1: dynamin-related protein 1; FIS1: mitochondrial fission protein 1; BAP31: B-cell receptor-associated protein 31; PERK: RNA-dependent protein kinase (PKR)-like ER kinase; ERO1α: ER oxidoreductin 1; LRRK2: leucine-rich repeat kinase 2; STING: stimulator of interferon genes; NLRP3: nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3; MAVS: mitochondrial antiviral signaling protein; ACAT1: acyl-CoA: cholesterol acyl-transferase 1; ASCL4: acyl-CoA synthetase 4; ERLIN2: endoplasmic reticulum lipid raft-associated protein 2; PSS1: phosphatidylserine synthase 1; PSS2: phosphatidylserine synthase 2; PSD: phosphatidylserine decarboxylase; SIG1R: sigma-1 receptor; BiP/GRP78: glucose-regulated protein 78; SERCA: sarcoendoplasmic reticulum Ca2+ transport ATPase; IP3R: inositol 1,4,5-triphosphate receptors; GRP75: glucose-regulated protein 75; VDAC: voltage-dependent anion channel; MCU: mitochondrial calcium uniporter; PtdCho: Phosphatidylcholine; PtdEtn: Phosphatidylethanolamine; PtdSer: Phosphatidylserine; αSyn: alpha-synuclein; ETC: electron transport chain.
Figure 2
Figure 2
αSyn binding partners associated with the MAM. αSyn has been shown to be directly bound to MAM tethers VAPB-PTPIP51, BAP31-FIS1, and IP3R-GRP75-VDAC and can be indirectly bound to MFN2. Selected proteins at the ER-facing and mitochondria-facing MAM domains are shown. Note that the illustration of αSyn–protein binding at MAMs is for illustrative purposes and does not indicate which domain of αSyn (N-, NAC-, C-terminus) is bound. Abbreviations: MIRO: Mitochondrial Rho GTPase; MFN2: Mitofusin-2; BCL2: B-cell lymphoma 2; TOM20: translocase of the outer mitochondrial membrane complex subunit 20; IP3R: inositol 1,4,5-triphosphate receptors; GRP75: glucose-regulated protein 75; VDAC: voltage-dependent anion channel; VAPB: vesicle-associated membrane protein B; PTPIP51: protein tyrosine phosphatase-interacting protein-51; FIS1: mitochondrial fission protein 1; BAP31: B-cell receptor-associated protein 31; GRP94: glucose-regulated protein 94; BiP/GRP78: glucose-regulated protein 78; PACS2: phosphofurin acidic cluster sorting protein 2.
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