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.

Glycosphingolipids within membrane contact sites influence their function as signaling hubs in neurodegenerative diseases

“…In these conditions, MCS dysfunction has either been linked to mutations that directly affect one of the tethering proteins or to altered activity of nontether components of the MCSs. Given that this subject has been extensively reviewed in several recent publications [ 20 , 23 , 75 , 76 , 77 , 78 , 79 ], here we cite only those examples that have been directly or indirectly linked to defects in tethering complexes functioning as lipid transporters at MCSs. For example, several genetic mutations affecting the activity of the VAPB isoform in MCSs (specifically those formed with ER membranes) appear to disrupt phospholipid homeostasis and Ca 2+ signaling, and to activate the ER stress response in a familial form of ALS, known as ALS type 8 [ 75 ].…”

Mitochondria-ER contact sites expand during mitosis

“… 1 , 2 , 3 The exchange of ions and lipids at MCS argues for a role in regulating metabolic fluxes. The functional importance of MCS is highlighted by their emerging roles in multiple diseases including neurodegenerative disorders 4 and cancer. 5 …”

Seipin deficiency-induced lipid dysregulation leads to hypomyelination-associated cognitive deficits via compromising oligodendrocyte precursor cell differentiation

“…Knockout of lipogenic enzymes gene (e.g., Fa2h , Fasn ) in mice disrupts OL differentiation and causes late-onset myelin splitting or demyelination [ 31 , 32 ]. Moreover, in Alzheimer’s disease, and Parkinson’s disease, Seipin expression decreased, accompanied by lipid dysregulation and myelin deficits [ 33 – 36 ], All those evidences suggest Seipin, as a vital lipid metabolism mediator, play essential role in myelin plasticity. However, whether and how Seipin deficiency-leaded neurobehavioral impairments is underlined by lipid dysregulation and its consequent myelin abnormalities remains to be elucidated.…”