Biology subjects

Brzozowski, C. F.

Publications and source records attributed to Brzozowski, C. F..

3 recordsLinked to original sources

bioRxiv2026

α-Synuclein aggregates in corticostriatal terminals impair glutamatergic transmission in the absence of neurodegeneration

Substantia nigra pars compacta dopamine neuron loss and Lewy pathology, aggregates of -synuclein, characterize Parkinsons disease and Dementia with Lewy Bodies. Lewy pathology localizes to cortical neurons, and is found as Lewy neurites in the striatum, but its effects on excitatory synaptic function are just beginning to be understood. Corticostriatal projections regulate motor and cognitive behaviors impaired in these disorders. Here, -synuclein aggregation was induced in mouse M2 cortex, a vulnerable region in human disease. Early after initiation, aggregates localized to corticostriatal vesicular glutamate transporter 1 (vGLUT1)-positive terminals, with sparing of spiny projection neuron (SPN) soma, and dopamine terminals and neurons. Corticostriatal presynaptic aggregates significantly impaired glutamatergic transmission, without overt cortical neuron loss, and were associated with decreased synaptic density and volume. Thus, formation of presynaptic -synuclein aggregates impairs corticostriatal function without degeneration of cortical neurons or striatal dopamine terminals, suggesting pathologic -synuclein is sufficient for synaptic loss. Our findings also point to early synaptic dysfunction as a therapeutic target in Lewy body diseases.

neuroscience↗

bioRxiv2024

Cortico-amygdala synaptic structural abnormalities produced by templated aggregation of α-synuclein

Parkinsons disease (PD) and Dementia with Lewy bodies (DLB) are characterized by neuronal -synuclein (-syn) inclusions termed Lewy Pathology, which are abundant in the amygdala. The basolateral amygdala (BLA), in particular, receives projections from the thalamus and cortex. These projections play a role in cognition and emotional processing, behaviors which are impaired in -synucleinopathies. To understand if and how pathologic -syn impacts the BLA requires animal models of -syn aggregation. Injection of -synuclein pre-formed fibrils (PFFs) into the striatum induces robust -synuclein aggregation in excitatory neurons in the BLA that corresponds with reduced contextual fear conditioning. At early time points after aggregate formation, cortico-amygdala excitatory transmission is abolished. The goal of this project was to determine if -syn inclusions in the BLA induce synaptic degeneration and/or morphological changes. In this study, we used C57BL/6J mice injected bilaterally with PFFs in the dorsal striatum to induce -syn aggregate formation in the BLA. A method was developed using immunofluorescence and three-dimensional reconstruction to analyze excitatory cortico-amygdala and thalamo-amygdala presynaptic terminals closely juxtaposed to postsynaptic densities. The abundance and morphology of synapses were analyzed at 6- or 12-weeks post-injection of PFFs. -Syn aggregate formation in the BLA did not cause a significant loss of synapses, but cortico-amygdala and thalamo-amygdala presynaptic terminals and postsynaptic densities with aggregates of -synuclein show increased volumes, similar to previous findings in human DLB cortex, and in non-human primate models of PD. Transmission electron microscopy showed that PFF-injected mice showed reduced intervesicular distances similar to a recent study showing phospho-serine-129 -synuclein increases synaptic vesicle clustering. Thus, pathologic -synuclein causes major alterations to synaptic architecture in the BLA, potentially contributing to behavioral impairment and amygdala dysfunction observed in synucleinopathies.

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↗