Search

Copy number mutations implicate excess production of α-synuclein as a possibly causative factor in Parkinson's disease (PD). Using an unbiased screen targeting endogenous gene expression, we discovered that the β2-adrenoreceptor (β2AR) is a regulator of the α-synuclein gene (SNCA). β2AR ligands modulate SNCA transcription through histone 3 lysine 27 acetylation of its promoter and enhancers. Over 11 years of follow-up in 4 million Norwegians, the β2AR agonist salbutamol, a brain-penetrant asthma medication, was associated with reduced risk of developing PD (rate ratio, 0.66; 95% confidence interval, 0.58 to 0.76). Conversely, a β2AR antagonist correlated with increased risk. β2AR activation protected model mice and patient-derived cells. Thus, β2AR is linked to transcription of α-synuclein and risk of PD in a ligand-specific fashion and constitutes a potential target for therapies.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive accumulation in selected neurons of protein inclusions containing [Alpha]-synuclein and ubiquitin. Rare inherited forms of PD are caused by autosomal dominant mutations in [Alpha]-synuclein or by autosomal recessive mutations in parkin, an E3 ubiquitin ligase. We hypothesized that these two gene products interact functionally, namely, that parkin ubiquitinates [Alpha]-synuclein normally and that this process is altered in autosomal recessive PD. We have now identified a protein complex in normal human brain that includes parkin as the E3 ubiquitin ligase, UbcH7 as its associated E2 ubiquitin conjugating enzyme, and a new 22-kilodalton glycosylated form of [Alpha]-synuclein ([Alpha]Sp22) as its substrate. In contrast to normal parkin, mutant parkin associated with autosomal recessive PD failed to bind [Alpha]Sp22. In an in vitro ubiquitination assay, [Alpha]Sp22 was modified by normal but not mutant parkin into polyubiquitinated, high molecular weight species. Accordingly, [Alpha]Sp22 accumulated in a non-ubiquitinated form in parkin-deficient PD brains. We conclude that [Alpha]Sp22 is a substrate for parkin's ubiquitin ligase activity in normal human brain and that loss of parkin function causes pathological [Alpha]Sp22 accumulation. These findings demonstrate a critical biochemical reaction between the two PD-linked gene products and suggest that this reaction underlies the accumulation of ubiquitinated [Alpha]-synuclein in conventional PD., Parkinson's disease is a highly prevalent neurodegenerative disorder that causes progressive motor dysfunction, variable cognitive impairment, and shortened life expectancy (1). The molecular pathogenesis of PD remains unclear, but genetic [...]

Gene Dosage of the Amyloid Precursor Protein in Alzheimer's Disease THE DEPOSITION OF EXTRACELLULAR amyloid filaments within clusters of degenerating neurites (neuritic plaques) and in cerebral and meningeal blood vessels [...]

Amyloid β Protein Enhances the Survival of Hippocampal Neurons in Vitro IN ALZHEIMER'S DISEASE (AD), INSOLuble fibrils of B-amyloid (A4) protein accumulate cerebral blood vessels and in neuritic plaques. Within [...]

Synapse loss in Alzheimer's disease (AD) correlates with cognitive decline. Involvement of microglia and complement in AD has been attributed to neuroinflammation, prominent late in disease. Here we show in mouse models that complement and microglia mediate synaptic loss early in AD. C1q, the initiating protein of the classical complement cascade, is increased and associated with synapses before overt plaque deposition. Inhibition of C1q, C3, or the microglial complement receptor CR3 reduces the number of phagocytic microglia, as well as the extent of early synapse loss. C1q is necessary for the toxic effects of soluble b-amyloid (Ab) oligomers on synapses and hippocampal long-term potentiation. Finally, microglia in adult brains engulf synaptic material in a CR3-dependent process when exposed to soluble Ab oligomers. Together, these findings suggest that the complement-dependent pathway and microglia that prune excess synapses in development are inappropriately activated and mediate synapse loss in AD. [ABSTRACT FROM AUTHOR]