Biology subjects

Volpicelli-Daley, L. A.

Publications and source records attributed to Volpicelli-Daley, L. A..

3 recordsLinked to original sources

bioRxiv2022

Neuronopathic GBA1 L444P mutation accelerates glucosylsphingosine levels and formation of hippocampal alpha-synuclein inclusions

The most common genetic risk factor for Parkinsons disease (PD) is heterozygous mutations in the GBA1 gene which encodes for the lysosomal enzyme, glucocerebrosidase (GCase). GCase impairments are associated with an accumulation of abnormal -synuclein (-syn) called Lewy pathology, which characterizes PD. PD patients heterozygous for the GBA1 L444P mutation (GBA1+/L444P) have a 5.6-fold increased risk of cognitive impairments. In this study, we used GBA1+/L444P mice to determine the effects of this severe GBA1 mutation on lipid metabolism, expression of synaptic proteins, behavior, and -syn inclusion formation. GBA1+/L444P mice showed reduced GCase activity in limbic brain regions and expressed lower levels of hippocampal vGLUT1 compared to wildtype (GBA1+/+) mice. GBA+/L444P mice also demonstrated impaired fear conditioning, but no motor deficits. We show, using mass spectrometry, that mutant GCase and age increased levels of glucosylsphingosine (GlcSph), but not glucosylceramide (GlcCer), in the brains and serum of GBA1+/L444P mice. Aged GBA1+/+ mice also showed increased levels of GlcSph, and decreased GlcCer. To model disease pathology, templated -syn pathology was used. -Syn inclusions were increased in the hippocampus of GBA1+/L444P mice compared to GBA1+/+ mice, but not in the cortex, or substantia nigra pars compacta (SNc). Pathologic -syn did not cause a loss of dopamine neurons in the SNc. Treatment with a GlcCer synthase inhibitor prevented loss of cortical -syn inclusions, but not loss of dopamine neurons. Overall, these data suggest the critical importance to evaluate the contribution of hippocampal pathologic -syn and brain and serum glucosylsphingosine in synucleinopathies. SIGNIFICANCE STATEMENTSynucleinopathies, such as Parkinsons disease (PD) and Dementia with Lewy bodies (DLB), are both pathologically characterized by abnormal -synuclein (-syn). Mutant GBA1 is a risk factor for both PD and DLB where a reduction of glucocerebrosidase (GCase) activity is seen. Collectively, this indicates the significance of evaluating mutant GCase in synucleinopathies. Our data suggest the critical importance to evaluate the contribution of hippocampal pathologic -syn and brain and serum glucosylsphingosine (GlcSph) accumulation in synucleinopathies. Moreover, these pathologic outcomes may contribute to the nonmotor symptoms clinically observed in PD and DLB. Our findings highlight the importance of GlcSph as a relevant biomarker for future therapeutics.

neuroscience↗

bioRxiv2021

Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein

Pathologic inclusions composed of -synuclein called Lewy pathology are hallmarks of Parkinsons Disease (PD). Dominant inherited mutations in leucine rich repeat kinase 2 (LRRK2) are the most common genetic cause of PD. Lewy pathology is found in the majority of individuals with LRRK2-PD, particularly those with the G2019S-LRRK2 mutation. Lewy pathology in LRRK2-PD associates with increased non-motor symptoms such as cognitive deficits, anxiety, and orthostatic hypotension. Thus, understanding the relationship between LRRK2 and -synuclein could be important for determining the mechanisms of non-motor symptoms. In PD models, expression of mutant LRRK2 reduces membrane localization of - synuclein, and enhances formation of pathologic -synuclein, particularly when synaptic activity is increased. -Synuclein and LRRK2 both localize to the presynaptic terminal. LRRK2 plays a role in membrane traffic, including axonal transport, and therefore may influence -synuclein synaptic localization. This study shows that LRRK2 kinase activity influences -synuclein targeting to the presynaptic terminal. We used the selective LRRK2 kinase inhibitors, MLi-2 and PF-06685360 (PF-360) to determine the impact of reduced LRRK2 kinase activity on presynaptic localization of -synuclein. Expansion microscopy (ExM) in primary hippocampal cultures and the mouse striatum, in vivo, was used to more precisely resolve the presynaptic localization of -synuclein. Live imaging of axonal transport of -synuclein-GFP was used to investigate the impact of LRRK2 kinase inhibition on -synuclein axonal transport towards the presynaptic terminal. Reduced LRRK2 kinase activity increases -synuclein overlap with presynaptic markers in primary neurons, and increases anterograde axonal transport of - synuclein-GFP. In vivo, LRRK2 inhibition increases -synuclein overlap with glutamatergic, cortico-striatal terminals, and dopaminergic nigral-striatal presynaptic terminals. The findings suggest that LRRK2 kinase activity plays a role in axonal transport, and presynaptic targeting of -synuclein. These data provide potential mechanisms by which LRRK2-mediated perturbations of -synuclein localization could cause pathology in both LRRK2-PD, and idiopathic PD.

neuroscience↗

bioRxiv2021

Alpha-synuclein alters the faecal viromes of rats in a gut-initiated model of Parkinson's disease

Parkinsons disease (PD) is a chronic neurological disorder associated with the misfolding of alpha-synuclein (-syn) into Lewy body aggregates within nerve cells that contribute to their neurodegeneration. Recent evidence suggests -syn aggregation may begin in the gut and travel to the brain along the vagus nerve, with microbes a potential trigger initiating the misfolding of -syn. However, changes in the gut virome in response to -syn alterations have not been investigated. In this study, we show longitudinal changes in the faecal virome of rats administered either monomeric or preformed fibrils (PFF) of -syn directly into their enteric nervous system. Differential changes in rat viromes were observed when comparing monomeric and PFF -syn. The virome {beta}-diversity changes after -syn treatment were compounded by the addition of LPS as an adjunct. Changes in the diversity of rat faecal viromes were observed after one month and did not resolve within the studys five month observational period. Overall, these results suggest that microbiome alterations associated with PD may, partially, be reactive to host -syn associated changes.

microbiology↗