Inter-organellar Communication in Parkinson's and Alzheimer's Disease: Looking Beyond Endoplasmic Reticulum-Mitochondria Contact Sites

Abstract

Neurodegenerative diseases (NDs) are generally considered proteinopathies but whereas this may initiate disease in familial cases, onset in sporadic diseases may originate from a gradually disrupted organellar homeostasis. Herein, endolysosomal abnormalities, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and altered lipid metabolism are commonly observed in early preclinical stages of major NDs, including Parkinson's disease (PD) and Alzheimer's disease (AD). Among the multitude of underlying defective molecular mechanisms that have been suggested in the past decades, dysregulation of inter-organellar communication through the so-called membrane contact sites (MCSs) is becoming increasingly apparent. Although MCSs exist between almost every other type of subcellular organelle, to date, most focus has been put on defective communication between the ER and mitochondria in NDs, given these compartments are critical in neuronal survival. Contributions of other MCSs, notably those with endolysosomes and lipid droplets are emerging, supported as well by genetic studies, identifying genes functionally involved in lysosomal homeostasis. In this review, we summarize the molecular identity of the organelle interactome in yeast and mammalian cells, and critically evaluate the evidence supporting the contribution of disturbed MCSs to the general disrupted inter-organellar homeostasis in NDs, taking PD and AD as major examples.

Keywords: endolysosome; inter-organellar communication; lipid metabolism; membrane contact site; mitochondria; neurodegenerative disease.

Figure 1

Contact sites in yeast and mammalian cells. Known tethers and interactors are displayed for contacts involving the ER (magenta), mitochondria (green), vacuoles/endolysosomes (blue) and lipid droplets (yellow). Yeast versus mammalian interactors are separated where possible. Proteins identified in yeast are written in lowercase, while mammalian/human proteins are in capital letters. For more details, we refer to Table 1.

Figure 2

The organelle interactome in PD. PD-linked proteins (indicated in bold) are involved in the regulation of multiple contact sites, ranging from mitochondrial-late endo/lysosomal (mito-LE/Lys), endoplasmic reticulum-late endo/lysosomal (ER-LE/Lys), endoplasmic reticulum-lipid droplet (ER-LD), and mitochondrial-endoplasmic reticulum (MAMs) contacts. New hypothetical mediators and mechanisms are illustrated as well as established ones. LOF, loss-of-function.

Figure 3

The organelle interactome in AD. Contact sites between the ER and mitochondria (MAM) were linked to a physical interaction between MFN2 and PSEN2/γ-secretase, while ER-LE/Lys contacts may represent a primary root for organellar disruption through the generation of aggregation-prone Aβ in LE/Lys by PSEN2/γ-secretase. The illustrated observation that lysosomal Ca²⁺ is disrupted in AD supports this hypothesis. Contacts between the ER and the plasma membrane are additionally represented in order to illustrate disruption of Ca²⁺ homeostasis involving the capacitative SOCE mechanism, with a suggested interaction between PSEN1/γ-secretase and STIM1.