Molecular Mechanisms Underlying Synaptic and Axon Degeneration in Parkinson’s Disease

Gcwensa, Nolwazi Z.; Russell, Drèson L.; Cowell, Rita M.; Volpicelli‐Daley, Laura A.

doi:10.3389/fncel.2021.626128

Cited by 54 publications

(35 citation statements)

References 152 publications

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“…LRRK2 also plays a major role in membrane trafficking [ 25 , 69 ]. Defects in trafficking and targeting of α-synuclein to the correct membrane compartment within the neuron may influence its propensity to aggregate [ 70 ]. α-Synuclein primarily localizes to the presynaptic terminal [ 16 , 71 – 74 ] where it interacts with the SNARE complex to reduce synaptic vesicle exocytosis [ 13 , 14 ].…”

Section: Discussionmentioning

confidence: 99%

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

Brzozowski

Hijaz

Singh

et al. 2021

acta neuropathol commun

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Pathologic inclusions composed of α-synuclein called Lewy pathology are hallmarks of Parkinson’s 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 α-synuclein could be important for determining the mechanisms of non-motor symptoms. In PD models, expression of mutant LRRK2 reduces membrane localization of α-synuclein, and enhances formation of pathologic α-synuclein, particularly when synaptic activity is increased. α-Synuclein and LRRK2 both localize to the presynaptic terminal. LRRK2 plays a role in membrane traffic, including axonal transport, and therefore may influence α-synuclein synaptic localization. This study shows that LRRK2 kinase activity influences α-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 α-synuclein. Expansion microscopy (ExM) in primary hippocampal cultures and the mouse striatum, in vivo, was used to more precisely resolve the presynaptic localization of α-synuclein. Live imaging of axonal transport of α-synuclein-GFP was used to investigate the impact of LRRK2 kinase inhibition on α-synuclein axonal transport towards the presynaptic terminal. Reduced LRRK2 kinase activity increases α-synuclein overlap with presynaptic markers in primary neurons, and increases anterograde axonal transport of α-synuclein-GFP. In vivo, LRRK2 inhibition increases α-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 α-synuclein. These data provide potential mechanisms by which LRRK2-mediated perturbations of α-synuclein localization could cause pathology in both LRRK2-PD, and idiopathic PD.

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Section: Discussionmentioning

confidence: 99%

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

Brzozowski

Hijaz

Singh

et al. 2021

acta neuropathol commun

Self Cite

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“…Furthermore, synapse loss has been shown to occur early in the neurodegenerative process, for example in the retina of glaucoma models and patients, or in the brain of AD or PD models and patients (Selkoe, 2002;Della Santina et al, 2013;Purro et al, 2014;Bellucci et al, 2016;Subramanian and Tremblay, 2021). More specifically, a decrease in synaptic volume in of pre-and post-synapses has been reported in the striatum of PD patients (Bellucci et al, 2016;Reeve et al, 2018;Gcwensa et al, 2021). Of note, an age-related decrease of postsynaptic retinal proteins was also observed in the plexiform layers of Octodon degus, the only rodent with naturally occurring AD (Chang et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Characterizing the Retinal Phenotype of the Thy1-h[A30P]α-syn Mouse Model of Parkinson’s Disease

et al. 2021

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Despite decades of research, disease-modifying treatments of Parkinson’s disease (PD), the second most common neurodegenerative disease worldwide, remain out of reach. One of the reasons for this treatment gap is the incomplete understanding of how misfolded alpha-synuclein (α-syn) contributes to PD pathology. The retina, as an integral part of the central nervous system, recapitulates the PD disease processes that are typically seen in the brain, and retinal manifestations have emerged as prodromal symptoms of the disease. The timeline of PD manifestations in the visual system, however, is not fully elucidated and the underlying mechanisms are obscure. This highlights the need for new studies investigating retinal pathology, in order to propel its use as PD biomarker, and to develop validated research models to investigate PD pathogenesis. The present study pioneers in characterizing the retina of the Thy1-h[A30P]α-syn PD transgenic mouse model. We demonstrate widespread α-syn accumulation in the inner retina of these mice, of which a proportion is phosphorylated yet not aggregated. This α-syn expression coincides with inner retinal atrophy due to postsynaptic degeneration. We also reveal abnormal retinal electrophysiological responses. Absence of selective loss of melanopsin retinal ganglion cells or dopaminergic amacrine cells and inflammation indicates that the retinal manifestations in these transgenic mice diverge from their brain phenotype, and questions the specific cellular or molecular alterations that underlie retinal pathology in this PD mouse model. Nevertheless, the observed α-syn accumulation, synapse loss and functional deficits suggest that the Thy1-h[A30P]α-syn retina mimics some of the features of prodromal PD, and thus may provide a window to monitor and study the preclinical/prodromal stages of PD, PD-associated retinal disease processes, as well as aid in retinal biomarker discovery and validation.

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“…It has recently been recognized that presynaptic alterations play important roles in neurodegenerative diseases and that these changes occur in the early, prodromal phase of PD, preceding DA neuron loss (Gcwensa et al, 2021). Given that excessive glutamate release can lead to neurotoxicity and neuronal death (Wang et al, 2020), it is possible that an altered LRRK2 function in glutamatergic synapses onto SNc‐DA neurons contributes to G2019S‐linked PD pathology.…”

Section: Introductionmentioning

confidence: 99%

LRRK2‐G2019S mice display alterations in glutamatergic synaptic transmission in midbrain dopamine neurons

Skiteva

Yao

Sitzia

et al. 2022

Journal of Neurochemistry

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The progressive degeneration of dopamine (DA) neurons in the substantia nigra compacta (SNc) leads to the emergence of motor symptoms in patients with Parkinson's disease (PD). To propose neuroprotective therapies able to slow or halt the progression of the disease, it is necessary to identify cellular alterations that occur before DA neurons degenerate and before the onset of the motor symptoms that characterize PD. Using electrophysiological, histochemical, and biochemical approaches, we have examined if glutamatergic synaptic transmission in DA neurons in the SNc and in the adjacent ventral tegmental area (VTA) was altered in middle‐aged (10–12 months old) mice with the hG2019S point mutation (G2019S) in the leucine‐rich repeat kinase 2 (LRRK2) gene. G2019S mice showed increased locomotion and exploratory behavior compared with wildtype (WT) littermates, and intact DA neuron integrity. The intrinsic membrane properties and action potential characteristics of DA neurons recorded in brain slices were similar in WT and G2019S mice. Initial glutamate release probability onto SNc‐DA neurons, but not VTA‐DA neurons, was reduced in G2019S mice. We also found reduced protein amounts of the presynaptic marker of glutamatergic terminals, VGLUT1, and of the GluA1 and GluN1 subunits of AMPA and NMDA receptors, respectively, in the ventral midbrain of G2019S mice. These results identify alterations in glutamatergic synaptic transmission in DA neurons of the SNc and VTA before the onset of motor impairments in the LRRK2‐G2019S mouse model of PD.

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Molecular Mechanisms Underlying Synaptic and Axon Degeneration in Parkinson’s Disease

Cited by 54 publications

References 152 publications

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

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

Characterizing the Retinal Phenotype of the Thy1-h[A30P]α-syn Mouse Model of Parkinson’s Disease

LRRK2‐G2019S mice display alterations in glutamatergic synaptic transmission in midbrain dopamine neurons

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