As pathogenic Parkin mutations result in the defective clearance of damaged mitochondria, Parkin-dependent mitophagy is thought to be protective against the dopaminergic neurodegeneration observed in Parkinson’s disease. Recent studies, however, have demonstrated that Parkin can promote cell death in the context of severe mitochondrial damage by degrading the pro-survival Bcl-2 family member, Mcl-1. Therefore, Parkin may act as a ‘switch’ that can shift the balance between protective or pro-death pathways depending on the degree of mitochondrial damage. Here, we report that the Parkin interacting protein, Bcl-2-associated athanogene 5 (BAG5), impairs mitophagy by suppressing Parkin recruitment to damaged mitochondria and reducing the movement of damaged mitochondria into the lysosomes. BAG5 also enhanced Parkin-mediated Mcl-1 degradation and cell death following severe mitochondrial insult. These results suggest that BAG5 may regulate the bi-modal activity of Parkin, promoting cell death by suppressing Parkin-dependent mitophagy and enhancing Parkin-mediated Mcl-1 degradation.

Molecular chaperones are critical to maintaining intracellular proteostasis and have been shown to have a protective role against alpha-synuclein-mediated toxicity. Cochaperone proteins regulate the activity of molecular chaperones and connect the chaperone network to protein degradation and cell death pathways. Bcl-2 associated athanogene 5 (BAG5) is a co-chaperone that modulates proteostasis by inhibiting the activity of Heat shock protein 70 (Hsp70) and several E3 ubiquitin ligases, resulting in enhanced neurodegeneration in models of Parkinson's disease (PD). Here we identify a novel interaction between BAG5 and p62/sequestosome-1 (SQSTM1), suggesting that BAG5 may bridge the chaperone network to autophagy-mediated protein degradation. We found that BAG5 enhanced the formation of pathogenic alpha-synuclein oligomers and regulated the levels and subcellular distribution of p62. These results extend the role of BAG5 in alpha-synuclein processing and intracellular proteostasis.

Ischemic stroke affects millions of individuals worldwide and a high prevalence of survivors experience cognitive deficits. At present, the underlying mechanisms that drive post-stroke cognitive decline are not well understood. Microglia play a critical role in the post-stroke inflammatory response, but experimental studies show that an accumulation of chronically activated microglia can be harmful and associates with cognitive impairment. This study aimed to assess the effect of acute post-stroke minocycline treatment, a tetracycline derivative that readily crosses the blood-brain barrier and has been shown to inhibit microglia activation, on chronic microglia and astrocyte expression within both the infarct and remote white matter regions, as well as determine its effect on various domains of cognitive function post-stroke. Nine-month-old male rats received an injection of endothelin-1 into the right dorsal striatum to induce a transient focal ischemic stroke, and then were treated with minocycline or saline for 4 days post-stroke. Rats were tested using a series of lever-pressing tasks and the Morris water maze to assess striatal-based learning, cognitive flexibility, and spatial learning and reference memory. We found that minocycline-treated rats had smaller stroke-induced infarcts, less microglia activation in the infarct area and less microglia activation in remote white matter regions compared to saline-treated rats at 28 days post-stroke. The behavioural testing results differed according to the cognitive domain; whereas minocycline-treated rats trended towards improved striatal-based learning in a lever-pressing task, but cognitive flexibility was unaffected during the subsequent set-shifting task. Furthermore, minocycline treatment unexpectedly impaired spatial learning, yet it did not alter reference memory. Collectively, we show that post-stroke minocycline treatment can reduce chronic microglia activation even in remote brain regions, with domain-specific effects on cognitive function.

Current literature indicates a potential synergistic interaction between stroke and Alzheimer’s disease (AD). White matter (WM) inflammation, which is commonly triggered by cerebrovascular disease and AD, disrupts the normal function of white matter; and can trigger and exacerbate dementia‐type symptoms such as memory loss and executive dysfunction. Recent work in our lab demonstrated, for the first time, a link between stroke, AD‐related pathology, and WM inflammation. A unilateral lacunar stroke induction in a comorbid rat model of AD and stroke resulted in microglial activation within the WM tracts and subsequent impairment in behavioural flexibility, an important component of executive function. As such, the aim of the current study was to evaluate the effect of microglia targeting on WM pathology, executive function, learning, and memory in the co‐morbid rat model of AD (TgAPP21) and stroke. Minocycline, a tetracycline‐class antibiotic and an anti‐inflammatory drug, has been shown to decrease apoptosis, inflammation, and microglial activation following cerebrovascular injury. To study the behavioural outcomes of minocycline treatment, TgAPP21 rats received an endothelin‐1‐induced subcortical stroke at the age of 8 months. Following stroke, animals received intraperitoneal injections of minocycline or saline twice daily for four days to supress microglial activation. Cognitive behavioural flexibility post‐stroke was analyzed using set‐shifting operant conditioning test, while spatial learning and memory were assessed using Morris water maze. Immunohistochemistry was performed to evaluate the extent of microglial activation by detection of OX‐6 positive microglia in corpus callosum, internal capsule, and hippocampus. Minocycline treatment significantly decreased the number of errors committed by TgAPP21 rats on the visual cue component of the set‐shifting test, suggesting improved learning of the original visual cue task. However, minocycline also impaired animals’ ability to undergo an extra‐dimensional strategy shift from the original visual cue to a new spatial cue task, suggesting impaired behavioural flexibility. Further, minocycline treatment showed no significant effect on learning and memory of the Morris water maze task in TgAPP21 rats. Collectively, the data indicate that minocycline has distinct effects on the learning component of set‐shifting and Morris water maze tests, though further histological evaluation of OX‐6 positive microglia within WM tracts and hippocampus will contextualize current findings. Support or Funding Information Natural Sciences and Engineering Research Council (NSERC), Canadian Institutes of Health Research (CIHR), Canadian Foundation for Innovation (CFI), Canadian Consortium for Neurodegeneration and Aging (CCNA)

Выходные данные статьи и справка о публикации: в день оплаты статьи Рассылка печатных журналов и оттисков: 18.09.2021 Педагогические науки Психологические науки Научный журнал «Universum: психология и образование» Рубрики журнала ПОДРОБНЕЕ НА 7UNIVERSUM.COM