We have shown that multiple sclerosis (MS) and endoplasmic reticulum (ER) stress induce Rab32, an ER/mitochondria-localized small GTPase. High levels of both dominant-active (Q85L) or dominant-inactive (T39N) Rab32 are toxic to neurons. While Rab32Q85L interacts with its effector Drp1 to promote mitochondria fission, it is unclear how Rab32T39N could result as toxic to neurons. Given the perinuclear clustering of mitochondria observed upon transfection of inactive Rab32, we hypothesized Rab32T39N could stall mitochondria within neurites. The movement of mitochondria depends on kinesin-binding Miro proteins. High cytosolic [Ca] is bound by an EF hand motif within Miro proteins, resulting in mitochondrial arrest. Consistent with increased cytosolic [Ca], expression of Rab32T39N arrests mitochondria movement within neurites.
Changes in high-affinity nicotinic acetylcholine receptors are intricately connected to cognitive impairment in Alzheimer's Disease (AD). While preclinical work suggests a possible protective and cognitive-enhancing role for the auxiliary nicotinic α5 subunit, mRNA expression of the CHRNA5 gene has not been closely examined in the context of human aging and dementia. Here, we investigate the impact of two common SNPs predicted to have different effects on the nicotinic α5 subunit: the function-compromising rs16969968 and the expression-altering rs1979905. We analyzed data from human prefrontal cortex (922 subjects with matched genotypic and post-mortem RNA sequencing, including 22 subjects with single-nucleus data) of elderly participants in the Religious Orders Study and Memory and Aging Project (ROS/MAP). We tested the impact of SNP haplotypes on prefrontal expression of CHRNA5 as well as that of SNPs in its receptor partners: CHRNA4 and CHRNB2. In the context of cognition and neuropathology, we observed a significant negative association between the high CHRNA5-expressing rs1979905A2 genotype and β-amyloid load in the prefrontal cortex. Our analyses revealed that the greatest abundance of CHRNA5 expression was in chandelier neurons, a sparse but disproportionately-powerful set of interneurons, in addition to layer 5 and 6 pyramidal neurons. In subjects with functionally-unaltered CHRNA5, the proportion of chandelier cells in the prefrontal cortex shows resilience to β-amyloid load, but this resilience is diminished in subjects homozygous for the minor allele of the CHRNA5 missense SNP rs16969968. Taken together, these findings urge further investigation into the role of CHRNA5 and chandelier cells in AD neuroprotection.
Changes in high-affinity nicotinic acetylcholine receptors are intricately connected to neuropathology in Alzheimer’s Disease (AD). Protective and cognitive-enhancing roles for the nicotinic α5 subunit have been identified, but this gene has not been closely examined in the context of human aging and dementia. Therefore, we investigate the nicotinic α5 gene CHRNA5 and the impact of relevant single nucleotide polymorphisms (SNPs) in prefrontal cortex from 922 individuals with matched genotypic and post-mortem RNA sequencing in the Religious Orders Study and Memory and Aging Project (ROS/MAP). We find that a genotype robustly linked to expression of CHRNA5 (rs1979905A2) predicts significantly reduced β-amyloid load in prefrontal cortex. Yet, co-expression analysis shows a clear dissociation between expression of CHRNA5 and other cholinergic genes, suggesting a distinct cellular expression profile for the human nicotinic α5 subunit. Consistent with this prediction, single nucleus RNA sequencing from 22 individuals reveals disproportionately-elevated CHRNA5 expression in chandelier cells. These interneurons are enriched in amyloid-binding proteins and also play a vital role in excitatory/inhibitory (E/I) balance. Cell-type proportion analysis demonstrates that chandelier cells have increased amyloid vulnerability in individuals homozygous for the missense CHRNA5 SNP (rs16969968A2) that impairs function/trafficking of nicotinic α5-containing receptors. These findings suggest that CHRNA5 and its nicotinic α5 subunit exert a neuroprotective role in aging and Alzheimer's disease potentially centered on chandelier interneurons.
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