REST Protects Dopaminergic Neurons from Mitochondrial and α-Synuclein Oligomer Pathology in an Alpha Synuclein Overexpressing BAC-Transgenic Mouse Model.

Alpha-synuclein pathology is associated with dopaminergic neuronal loss in the substantia nigra (SN) of Parkinson's patients. Working across human and mouse models, we investigated mechanisms by which the accumulation of soluble α-synuclein oligomers leads to neurodegeneration. Biochemical analysis of the midbrain of α-synuclein overexpressing BAC-transgenic male and female mice revealed age- and region-dependent mitochondrial dysfunction and accumulation of damaged proteins downstream of the RE1 Silencing Transcription Factor (REST).

Proteomic Profiling of Mitochondrial-Derived Vesicles in Brain Reveals Enrichment of Respiratory Complex Sub-assemblies and Small TIM Chaperones.

The generation of mitochondrial-derived vesicles (MDVs) is implicated in a plethora of vital cell functions, from mitochondrial quality control to peroxisomal biogenesis. The discovery of distinct subtypes of MDVs has revealed the selective inclusion of mitochondrial cargo in response to varying stimuli. However, the true scope and variety of MDVs is currently unclear, and unbiased approaches have yet to be used to understand their biology.

Selective vulnerability in α-synucleinopathies.

Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy are neurodegenerative disorders resulting in progressive motor/cognitive deficits among other symptoms. They are characterised by stereotypical brain cell loss accompanied by the formation of proteinaceous aggregations of the protein α-synuclein (α-syn), being, therefore, termed α-synucleinopathies. Although the presence of α-syn inclusions is a common hallmark of these disorders, the exact nature of the deposited protein is specific to each disease.

Alpha-Synuclein Proximity Ligation Assay (AS-PLA) in Brain Sections to Probe for Alpha-Synuclein Oligomers.

Alpha-synuclein oligomers are thought to be toxic mediators of Parkinson's disease and other alpha-synucleinopathies, but their histological detection in situ in diseased brain has been a challenge in the field for some time. Here we describe a method, the alpha-synuclein proximity ligation assay (AS-PLA), to detect alpha-synuclein oligomers in paraffin-embedded brain sections. Using AS-PLA previously unobserved alpha-synuclein oligomeric pathology is revealed.

Alpha-synuclein oligomers: a new hope.

Alpha-synuclein is a protein implicated in Parkinson's disease and thought to be one of the main pathological drivers in the disease, although it remains unclear how this protein elicits its neurotoxic effects. Recent findings indicate that the assembly of toxic oligomeric species of alpha-synuclein may be one of the key processes for the pathology and spread of the disease. The absence of a sensitive in situ detection method has hindered the study of these oligomeric species and the role they play in the human brain until recently.

Presenting mitochondrial antigens: PINK1, Parkin and MDVs steal the show.

In a recent paper published in Cell, Matheoud et al. demonstrated that, in response to cellular stress, self-antigens can be extracted from mitochondria via mitochondrial-derived vesicles and presented at the cell surface to trigger an immune response; this pathway, termed mitochondrial antigen presentation (MitAP), is repressed by PINK1 and Parkin. These findings implicate autoimmune mechanisms in Parkinson's disease.

Defending the mitochondria: The pathways of mitophagy and mitochondrial-derived vesicles.

Mitochondria are the powerhouses for the cell, consuming oxygen to generate sufficient energy for the maintenance of normal cellular processes. However, a deleterious consequence of this process are reactive oxygen species generated as side-products of these reactions. As a means to protect mitochondria from damage, cells and mitochondria have developed a wide-range of mitochondrial quality control mechanisms that remove damaged mitochondrial cargo, enabling the mitochondria to repair the damage and ultimately restore their normal function.