MAM dysfunction is a common trait in neurodegenerative pathologies Recently, numerous evidences accumulated suggesting that MAM dysfunction contributes to the neurodegenerative processes in AD, PD, ALS, or HD112–114. In AD, both presenilin-1 and presenilin-2—the two major components of the ?-secretase complex that processes amyloid precursor protein (APP) to release amyloid-ß proteins (Aß) and that can be mutated in familial forms of AD—are present in MAMs115 (Fig. 1). MAMs are a site of production of Aß and this is consistent with the localization of presenilins in these regions116–118. Moreover, mutations of presenilins are a cause of familial forms of AD with early onset and mutant presenilins are catalytic loss-of-function mutants119. Both loss of presenilins and expression of mutant presenilins have been shown to affect ER–mitochondria associations and related functions116. Moreover, MAM are particularly sensitive to the neurodegenerative process since treatment of neurons with Aß affects ER–mitochondria contacts; alterations of ER–mitochondria association and function are seen in APP transgenic mouse models; and small interfering RNA knockdown of MAM proteins (S1R, phosphofurin acidic cluster sorting protein-2) results in neurodegeneration while MAM proteins are upregulated in AD mouse models95. Finally, the e4 allele of apolipoprotein E—ApoE4, the main genetic risk factor for AD—upregulates MAM activity120.
In PD, the neurodegenerative process affecting dopaminergic neurons from the nigro-striatal pathway is characterized by accumulation of pathological a-synuclein protein. A subpopulation of a-synuclein resides at the MAM121 (Fig. 1) and mutations in a-synuclein cause an alteration in the regulation of MAM function121.
In ALS, an hyper-phosphorylated, ubiquitinated, and cleaved form of transactive response DNA-binding protein 43?kDa (TDP-43) is the major pathological protein in frontotemporal dementia and ALS122. Pathological TDP-43 induces activation of glycogen synthase kinase-3ß and perturbs ER–mitochondria associations by impacting VAPB–PTPIP51 bridges91 (Fig. 1). TDP-43 downregulates MFN levels in Drosophila (J.C. Lievens, personal communication) and mouse models. Decreased MFN1/MFN2 levels are also reported in ALS patient biopsies and in a mouse model expressing wild-type TDP-43123,124. Moreover, a mutation of the MAM protein S1R may be responsible for familial ALS cases125,126 (Fig. 1). Loss of S1R leads to motor neuron degeneration in vitro127.
Alterations of ER–mitochondria associations may also occur in HD, but further research is required to provide stronger evidence. For instance, upregulation of striatal S1R was reported in YAC HD mice and HD patients (Ryskamp et al., Neurobiol Dis 2017), but it is unclear whether these alterations are causal mechanisms or compensatory regulations.
However, evidences are clearly accumulating showing that pathological proteins, responsible for the toxicity observed in neurodegenerative pathologies, particularly accumulate within MAM and that the concomitant/subsequent MAM alterations observed participate in the resulting toxicity.
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Conclusions The aim of this review was to integrate WS as a novel neurodegenerative MAMpathy together with AD, PD, HD, and ALS112–114. Indeed, CISD2 has been shown to play a role in ER–mitochondria Ca2+ signaling and regulation of autophagy and CISD2 deficient leads to ER stress and apoptosis. In addition, WFS1 regulate ER Ca2+ homeostasis by controlling the expression level of SERCA2b and WFS1 deficiency leads to ER stress and cell death. Since the majority of the case of NDs is sporadic and since WS is a rare genetic disorder, WS may be useful for the understanding of MAMs in a broader context. Finally, either in classical ND or in WS, there is a defect in MAMs and the presence of ER stress. It should be interesting to determine whether these two phenomena are tightly linked or are two independent mechanisms responsible for the pathology.
