There's Something Wrong with my MAM; the ER-Mitochondria Axis and Neurodegenerative Diseases

Abstract

Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis with associated frontotemporal dementia (ALS/FTD) are major neurodegenerative diseases for which there are no cures. All are characterised by damage to several seemingly disparate cellular processes. The broad nature of this damage makes understanding pathogenic mechanisms and devising new treatments difficult. Can the different damaged functions be linked together in a common disease pathway and which damaged function should be targeted for therapy? Many functions damaged in neurodegenerative diseases are regulated by communications that mitochondria make with a specialised region of the endoplasmic reticulum (ER; mitochondria-associated ER membranes or 'MAM'). Moreover, several recent studies have shown that disturbances to ER-mitochondria contacts occur in neurodegenerative diseases. Here, we review these findings.

Keywords: Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis/fronto-temporal dementia; endoplasmic reticulum; mitochondria; mitochondria associated ER membranes.

Figure 1

Electron Microscope Images of Endoplasmic Reticulum (ER)-–Mitochondria Contacts in NSC34 Motor Neuron Cells. A control cell is shown (CTRL) (A) along with a cell transfected with the tethering proteins vesicle-associated membrane protein-associated protein B (VAPB) and protein tyrosine phosphatase interacting protein 51 (PTPIP51) (B) . Some selected ER–mitochondria associations are highlighted in red. Transfection of VAPB and PTPIP51 dramatically increases ER–mitochondria associations. (C) A high-magnification image of a mitochondrion with associated ER in a VAPB/PTPIP51 co-transfected cell; putative tethering structures are discernible connecting the two organelles (arrowheads). Scale bars = 500 nm (A,B) and 100 nm (C).

Figure 2

Proposed Endoplasmic Reticulum (ER)–Mitochondria Tethering Protein Complexes. (A) Inositol 1,4,5-trisphosphate (IP3) receptors (IP₃R) and voltage-dependent anion channel (VDAC) interact via GRP75. (B) ER-located mitofusin 2 interacts with mitochondrial mitofusin1/2 (Mfn1, Mfn2). (C) Vesicle-associated membrane protein-associated protein B (VAPB) binds to protein tyrosine phosphatase interacting protein 51 (PTPIP51). (D) (Bap31) binds to Fission 1 homologue (Fis1).

Figure 3

Tar DNA-Binding Protein 43 (TDP-43) Loosens Endoplasmic Reticulum (ER)–Mitochondria Associations in Amyotrophic Lateral Sclerosis with Associated Frontotemporal Dementia (ALS/FTD). (A) Normal situation. (B) Disease situation. TDP-43 induces activation glycogen synthase kinase 3β (GSK-3β), which then disrupts binding of vesicle-associated membrane protein-associated protein B (VAPB) to protein tyrosine phosphatase interacting protein 51 (PTPIP51) to reduce ER–mitochondria associations and Ca²⁺ exchange between the two organelles.

Figure 4

Disruption to Endoplasmic Reticulum (ER)–Mitochondria Associations Provides a Mechanism by which many of the Disparate Pathological Features of Neurodegenerative Diseases Might Arise.