Human leukocyte antigen-DR induction and lymphocyte infiltrates in the brains of patients with Parkinson disease (PD) and the presence in serum of α-synuclein (α-syn)-specific antibodies suggest that the peripheral immune system may have an active role in the progression of PD. We designed a vaccination strategy to attempt to control these processes and mediate protection against disease progression in a rat PD model. Using a recombinant adeno-associated viral vector, we unilaterally overexpressed human α-syn in the rat substantia nigra to induce a progressive neuropathologic process. Prior to stereotactic delivery of the viral vector, animals were vaccinated with recombinant α-syn (asyn). This resulted in a high-titer anti-α-syn antibody response on α-syn overexpression; the accumulation of CD4-positive, MHC II-positive ramified microglia in the substantia nigra; long-lasting infiltration of CD4-positive, Foxp3-positive cells throughout the nigrostriatal system; and fewer pathologic aggregates in the striatum versus control animals that had received a mock vaccine. A long-term increase in GDNF levels in the striatum and IgG deposition in α-syn-overexpressing cells and neurites in the substantia nigra were also observed. Together, these results suggest that a protective vaccination strategy results in induction of regulatory T cells and distinctly activated microglia, and that this can induce immune tolerance against α-syn.

Fronto-temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two related and incurable neurodegenerative diseases. Features of these diseases include pathological protein inclusions in affected neurons with TAR DNA-binding protein 43 (TDP-43), dipeptide repeat proteins derived from the C9ORF72 gene, and fused in sarcoma (FUS) representing major constituent proteins in these inclusions. Mutations in C9ORF72 and the genes encoding TDP-43 and FUS cause familial forms of FTD/ALS which provides evidence to link the pathology and genetics of these diseases. A large number of seemingly disparate physiological functions are damaged in FTD/ALS. However, many of these damaged functions are regulated by signalling between the endoplasmic reticulum and mitochondria, and this has stimulated investigations into the role of endoplasmic reticulum-mitochondria signalling in FTD/ALS disease processes. Here, we review progress on this topic.

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Zbtb11 is a conserved transcription factor mutated in families with hereditary intellectual disability. Its precise molecular and cellular functions are currently unknown, precluding our understanding of the aetiology of this disease. Using a combination of functional genomics, genetic and biochemical approaches, here we show that Zbtb11 plays essential roles in maintaining the homeostasis of mitochondrial function. Mechanistically, we find Zbtb11 facilitates the recruitment of nuclear respiratory factor 2 (NRF-2) to its target promoters, activating a subset of nuclear genes with roles in the biogenesis of respiratory complex I and the mitoribosome. Genetic inactivation of Zbtb11 resulted in a severe complex I assembly defect, impaired mitochondrial respiration, mitochondrial depolarisation, and ultimately proliferation arrest and cell death. Experimental modelling of the pathogenic human mutations showed these have a destabilising effect on the protein, resulting in reduced Zbtb11 dosage, downregulation of its target genes, and impaired complex I biogenesis. Our study establishes Zbtb11 as an essential mitochondrial regulator, improves our understanding of the transcriptional mechanisms of nuclear control over mitochondria, and may help to understand the aetiology of Zbtb11-associated intellectual disability.

Zbtb11 is a conserved transcription factor mutated in families with hereditary intellectual disability.Its precise molecular and cellular functions are currently unknown, precluding our understanding of the aetiology of this disease. Using a combination of functional genomics, genetic and biochemical approaches here we show that Zbtb11 plays essential roles in maintaining the homeostasis of mitochondrial function. Mechanistically, we find Zbtb11 facilitates the recruitment of Nuclear Respiratory Factor 2 (NRF-2) to its target promoters, activating a subset of nuclear genes with roles in the biogenesis of respiratory complex I and the mitoribosome. Genetic inactivation of Zbtb11 resulted in a severe complex I assembly defect, impaired mitochondrial respiration, mitochondrial depolarisation, and ultimately proliferation arrest and cell death. Experimental modelling of the pathogenic human mutations showed these have a destabilising effect on the protein, resulting in reduced Zbtb11 dosage, down-regulation of its target genes, and impaired complex I biogenesis.Our study establishes Zbtb11 as a novel essential mitochondrial regulator, improves our understanding of the transcriptional mechanisms of nuclear control over mitochondria, and provides a rationale for the aetiology of Zbtb11-associated intellectual disability.ETC complexes (I, III and IV) couple substrate oxidation with proton extrusion from the mitochondrial matrix into the intermembrane space, thus creating an electrochemical gradient across the mitochondrial inner membrane which forces protons back into the matrix mainly through complex V (ATP synthase), driving the synthesis of ATP (Schultz & Chan, 2001). While mitochondria are ubiquitous organelles, tissues with high energy demands, such as brain and muscle, are particularly reliant on the activity of the ETC, and these are usually disproportionally affected in mitochondrial diseases. Nevertheless, because the activity of the ETC is also vital for regenerating the cellular pool of redox cofactors that catalyse a number of other metabolic reactions (Birsoy et al, 2015;Sullivan et al, 2015), it is becoming increasingly evident that a functional ETC is essential for all proliferating cells, irrespective of their ATP consumption (Yao et al, 2019).Mitochondria possess their own genome (mtDNA) and transcription machinery, as well as a specialised organellar ribosome (the mitoribosome). While the mtDNA encodes a small number of core subunits of the OXPHOS complexes, the majority of the mitochondrial proteome is encoded in the nuclear genome (nDNA). Mitochondrial biogenesis and function are therefore controlled to a significant extent through transcriptional regulation of nuclear genes. A number or transcription factors have been implicated in the regulation of nuclear-encoded mitochondrial genes, some of which are essential while others have modulatory roles important mainly in specific cell types or in conditions of increased energy demand (Fernandez-Marcos & Auwerx, 2011;Scarpulla et al, 2012).The nuclear re...