Biology subjects

Dues, D. J.

Publications and source records attributed to Dues, D. J..

3 recordsLinked to original sources

bioRxiv2024

Neuropathology in an α-synuclein preformed fibril mouse model occurs independent of the Parkinson's disease-linked lysosomal ATP13A2 protein

Loss-of-function mutations in the ATP13A2 (PARK9) gene are implicated in early-onset autosomal recessive Parkinsons disease (PD) and other neurodegenerative disorders. ATP13A2 encodes a lysosomal transmembrane P5B-type ATPase that is highly expressed in brain and specifically within the substantia nigra. Recent studies have revealed its normal role as a lysosomal polyamine transporter, although its contribution to PD-related pathology remains unclear. Cellular studies report that ATP13A2 can regulate -synuclein (-syn) secretion via exosomes. However, the relationship between ATP13A2 and -syn in animal models remains inconclusive. ATP13A2 knockout (KO) mice exhibit lysosomal abnormalities and reactive astrogliosis but do not develop PD-related neuropathology. Studies manipulating -syn levels in mice lacking ATP13A2 indicate minimal effects on pathology. The delivery of -syn preformed fibrils (PFFs) into the mouse striatum is a well-defined model to study the development and spread of -syn pathology. In this study, we unilaterally injected wild-type (WT) and homozygous ATP13A2 KO mice with mouse -syn PFFs in the striatum and evaluated mice for neuropathology after 6 months. The distribution, extent and spread of -syn aggregation in multiple regions of the mouse brain was largely independent of ATP13A2 expression. The loss of nigrostriatal pathway dopaminergic neurons and their nerve terminals induced by PFFs were equivalent in WT and ATP13A2 KO mice. Reactive astrogliosis was induced equivalently by -syn PFFs in WT and KO mice but was significantly higher in ATP13A2 KO mice due to pre-existing gliosis. We did not identify asymmetric motor disturbances, microglial activation, or axonal damage induced by -syn PFFs in WT or KO mice after 6 months. Although -syn PFFs induce an increase in lysosomal number in the substantia nigra in general, TH-positive dopaminergic neurons did not exhibit either increased lysosomal area or intensity, regardless of ATP13A2 genotype. Our study evaluating the spread of -syn pathology reveals no exacerbation of -syn pathology, neuronal loss, astrogliosis or motor deficits in ATP13A2 KO mice, suggesting that selective lysosomal abnormalities resulting from ATP13A2 loss do not play a major role in -syn clearance or propagation in vivo.

neuroscience↗

bioRxiv2023

Formation of templated inclusions in a forebrain α-synuclein mouse model is independent of LRRK2

Leucine-rich repeat kinase 2 (LRRK2) and -synuclein share enigmatic roles in the pathobiology of Parkinsons disease (PD). LRRK2 mutations are a common genetic cause of PD which, in addition to neurodegeneration, often present with abnormal deposits of -synuclein in the form of Lewy-related pathology. As Lewy-related pathology is a prominent neuropathologic finding in sporadic PD, the relationship between LRRK2 and -synuclein has garnered considerable interest. However, whether and how LRRK2 might influence the accumulation of Lewy-related pathology remains poorly understood. Through stereotactic injection of mouse -synuclein pre-formed fibrils (PFF), we modeled the spread of Lewy-related pathology within forebrain regions where LRRK2 is most highly expressed. The impact of LRRK2 genotype on the formation of -synuclein inclusions was evaluated at 1-month post-injection. Neither deletion of LRRK2 nor G2019S LRRK2 knockin appreciably altered the burden of - synuclein pathology at this early timepoint. These observations fail to provide support for a robust pathophysiologic interaction between LRRK2 and -synuclein in the forebrain in vivo. There was, however, a modest reduction in microglial activation induced by PFF delivery in the hippocampus of LRRK2 knockout mice, suggesting that LRRK2 may contribute to -synuclein-induced neuroinflammation. Collectively, our data indicate that the pathological accumulation of -synuclein in the mouse forebrain is largely independent of LRRK2. HighlightsO_LIAdult mice accumulate -synuclein pathology in the hippocampus and cortex following stereotactic injection with -synuclein PFFs, with negligible influence of LRRK2 genotype. C_LIO_LIHippocampal and cortical -synuclein pathology elicits the concomitant accrual of phosphorylated tau, reactive astrogliosis, and microglial activation. C_LIO_LIAbsence of endogenous LRRK2 attenuates microglial activation in the dorsal hippocampus induced by PFFs, but not in the entorhinal cortex. C_LIO_LIAccumulation of -synuclein inclusions and related neuropathologic changes were strongly associated across the hippocampal dorsal-ventral axis, regardless of LRRK2 genotype. C_LI

neuroscience↗

bioRxiv2023

Hippocampal subfield vulnerability to α-synuclein pathology precedes neurodegeneration and cognitive dysfunction

Cognitive dysfunction is a salient feature of Parkinsons disease (PD) and Dementia with Lewy bodies (DLB). The onset of dementia reflects the spread of Lewy pathology throughout forebrain structures. The mere presence of Lewy pathology, however, provides limited indication of cognitive status. Thus, it remains unclear whether Lewy pathology is the de facto substrate driving cognitive dysfunction in PD and DLB. Through application of -synuclein fibrils in vivo, we sought to examine the influence of pathologic inclusions on cognition. Following stereotactic injection of -synuclein fibrils within the mouse forebrain, we measured the burden of -synuclein pathology at 1-, 3-, and 6-months post-injection within subregions of the hippocampus and cortex. Under this paradigm, the hippocampal CA2/3 subfield was especially susceptible to - synuclein pathology. Strikingly, we observed a drastic reduction of pathology in the CA2/3 subfield across time-points, consistent with the consolidation of -synuclein pathology into dense somatic inclusions followed by neurodegeneration. Silver-positive degenerating neurites were observed prior to neuronal loss, suggesting that this might be an early feature of fibril-induced neurotoxicity and a precursor to neurodegeneration. Critically, mice injected with -synuclein fibrils developed progressive deficits in spatial learning and memory. These findings support that the formation of -synuclein inclusions in the mouse forebrain precipitate neurodegenerative changes that recapitulate features of Lewy-related cognitive dysfunction. HighlightsO_LIMice injected with -synuclein fibrils develop hippocampal and cortical - synuclein pathology with a dynamic regional burden at 1-, 3-, and 6-months post-injection. C_LIO_LISilver-positive neuronal processes are an early and enduring degenerative feature of the fibril model, while extensive neurodegeneration of the hippocampal CA2/3 subfield is detected at 6-months post-injection. C_LIO_LIMice exhibit progressive hippocampal-dependent spatial learning and memory deficits. C_LIO_LIForebrain injection of -synuclein fibrils may be used to model aspects of Lewy-related cognitive dysfunction. C_LI

neuroscience↗