Martin Parent

Parkinson’s disease (PD) diagnosis is currently made by clinical observation of motor symptoms when around 50% of dopamine neurons in the substantia nigra pars compacta are already lost. Non-motor symptoms, such as vision problems, occur earlier during disease progression and could be caused by altered retinal functioning. Various techniques exist to detect retinal alterations and, therefore, could provide biomarkers for earlier diagnosis of PD. The aim of this project is to determine potential retinal biomarkers for PD by using electroretinography (ERG) and pupillometry. In vivo measurements were performed on four non-human primates, before and after they were rendered parkinsonian by administration of 1-méthyl-4-phényl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that induces degeneration of dopamine neurons. ERG results showed a significant increase in photopic b-wave implicit time and reduced oscillatory potential (OP) amplitudes in both photopic and scotopic conditions following MPTP administration. The post-illumination pupillary response showed a consistently larger pupil diameter post-MPTP. Post-mortem examination revealed a significant thinning of the outer nuclear retinal layer. Tyrosine hydroxylase and melanopsin-containing cells were reduced in MPTP-intoxicated monkeys. Altogether, these results indicate that MPTP intoxication leads to functional retinal changes detectable by ERG and pupillometry, possibly attributed to cellular alterations.

The aggregation of α-synuclein (α-SYN) into Lewy bodies (LBs) is a central event in the pathogenesis of Parkinson’s disease (PD) and related synucleinopathies ^1,2 . Despite significant advances in understanding α-SYN self-assembly, the precise sequence of early aggregation steps has not been directly visualized in living neurons. Here, we use an optogenetic-induced protein aggregation system with a high temporal resolution to monitor the onset of α-SYN assembly in neurons. We found that the initiation and accumulation of α-SYN aggregates occur predominantly at the lysosomal membrane, an event driven by the α-SYN N-terminus and modulated by the membrane-associated adaptor protein WD repeat-containing protein 44 (WDR44). Remarkably, we demonstrate that WDR44 knockdown markedly reduced de novo α-SYN aggregation in both neuronal cultures and in vivo, whereas WDR44 overexpression enhances α-SYN aggregation in PD patient-derived iPSC neurons. Consistent with its potential pathogenic involvement, WDR44 aberrantly accumulates in vivo and in the brains of PD patients, where it colocalizes with LB inclusions. Finally, we show that lysosome-associated α-SYN aggregates compromised lysosomal structure and function, leading to neuronal impairment, a phenotype worsened by WDR44 overexpression, linking early aggregation events to downstream toxicity. Together, these findings reveal the earliest dynamic stages of α-SYN oligomerization in living neurons and identify the WDR44-α-SYN interaction as a promising therapeutic target for reducing α-SYN pathology and enabling early intervention in PD.

Vesicular glutamate transporter 3 (VGluT3) is expressed in a large subset of serotonin (5-HT) neurons of the dorsal raphe nucleus (DRN), suggesting a potential for glutamate co-transmission. Although VGluT3 has been implicated in the physiology of several non-glutamatergic neuronal populations, its specific role in the organization and function of 5-HT axons remains unclear. Here, we used CRISPR-Cas9 mediated knockdown and viral overexpression of VGluT3 in DRN 5-HT neurons of adult mice to assess its contribution to synaptic architecture in the lateral hypothalamus (LHA) and to 5-HT-related behaviors. VGluT3 depletion did not significantly alter synaptic incidence or organization of 5-HT DRN terminals in the LHA. In contrast, VGluT3 overexpression increased the proportion of asymmetric synapses without changing the overall synaptic incidence. In behavioral assays, VGluT3 depletion impaired motor coordination and increased anxiety-like, repetitive, and social behavior, whereas VGluT3 overexpression selectively reduced repetitive behavior. Basal locomotion and depressive-like behaviors were unchanged by either manipulation. Together, these findings indicate that VGluT3 modulates both the structural organization and behavioral output of DRN 5-HT neurons, supporting a modulatory role for VGluT3-dependent signaling within 5-HT circuits.

The olfactory bulb (OB) is one of the few regions in the adult brain that receives newly generated neuronal precursors throughout the lifespan of animals. These neuronal precursors differentiate into OB interneurons, mostly granule cells (GCs), and integrate into the bulbar network by forming dendro-dendritic reciprocal synapses with OB principal neurons. The ultrastructural properties and plasticity of these synapses and whether they are distinct from those formed by early-born, resident GCs remain unknown. In the present study, we assessed the ultrastructural properties of dendro-dendritic reciprocal synapses formed by either adult-born or resident, early-born GCs with principal neurons in mice of both sexes and studied their plasticity following sensory deprivation and odor learning. The synapses formed by either adult-born or resident, early-born GCs with principal bulbar neurons were undistinguishable in terms of area, diameter, and aspect ratio. In contrast, the synapses formed by adult-born GCs were characterized by a smaller synaptic cleft and a larger density of total and docked synaptic vesicles than synapses formed by resident GCs. Sensory deprivation and odor learning decreased and increased, respectively, the overall density and the number of docked synaptic vesicles in adult-born and resident GCs forming synapses with principal neurons. Our results revealed important differences in the ultrastructural properties of synapses formed by interneurons born at distinct developmental stages and revealed their plasticity in response to sensory deprivation and odor learning.

Annually, around 23 million people worldwide suffer from brain disorders, with 14 million requiring surgery for issues such as brain tumors, traumatic brain injuries, and neurodegenerative diseases such as Parkinson’s disease (PD).¹ Our focus is on deep brain stimulation (DBS), a stereotactic neurosurgical procedure that involves implanting electrodes in specific brain regions to regulate abnormal neural activity.² This technique, introduced by Benabid,³ is primarily used to treat movement disorders such as PD, dystonia, and essential tremor. MRI is an essential part of neurosurgical planning, where a pre-operative MRI (pre-op MRI) of the patient’s head is used to identify critical targets. DBS targets vary according to the disorder being treated: for instance, the subthalamic nucleus (STN) and internal pallidum (GPi) are commonly targeted for PD, the ventral intermediate thalamic nucleus (VIM) for essential tremor, and the caudate nucleus (CD) and the internal capsule (IC) for severe forms of obsessive-compulsive disorder (OCD).^{4 – 7} Once the target of interest is identified in MR images, its stereotactic coordinates are determined relative to anatomical landmarks such as the anterior and posterior commissures and to the stereotaxic frame placed on the patient’s head. After identifying the target, final adjustments and confirmation of the target may be performed in the operating room through microelectrode recording (MER) and macrostimulation when available.⁵

Parkinson’s disease (PD) is characterized by the progressive loss of dopamine (DA) neurons of the substantia nigra pars compacta (SNc), leading to the appearance of debilitating motor symptoms, in addition to nonmotor symptoms.^1,2 This neurodegenerative disorder is incurable, and although some motor symptoms can be alleviated by the administration of the DA metabolic precursor levodopa, such pharmacotherapy eventually leads to adverse side effects in the form of dyskinesias, leaving very limited options for alternative treatments.^{3 – 6} As the second most common neurodegenerative disease next to Alzheimer’s disease (AD), it is a burden on healthcare services worldwide, especially with the rapidly increasing aging population.⁷ For this reason, research efforts are being made to find alternative ways to detect PD, alleviate its symptoms, slow its progression, and find a cure.

Objective: Parkinson's and Huntington's diseases are characterized by progressive neuronal loss. Previous studies using human postmortem tissues have shown the impact of neurodegenerative disorders on adult neurogenesis. The extent to which adult neural stem cells are activated in the subventricular zone and whether therapeutic treatments such as deep brain stimulation promote adult neurogenesis remains unclear. The goal of the present study is to assess adult neural stem cells activation and neurogenesis in the subventricular zone of patients with Huntington's and Parkinson's diseases who were treated or not by deep brain stimulation.Methods: Postmortem brain samples from Huntington's and Parkinson's disease patients who had received or not long‐term deep brain stimulation of the subthalamic nucleus were used.Results: Our results indicate a significant increase in the thickness of the subventricular zone and in the density of proliferating cells and activated stem cells in the brain of Huntington's disease subjects and Parkinson's disease patients treated with deep brain stimulation. We also observed an increase in the density of immature neurons in the brain of these patients.Interpretation: Overall, our data indicate that long‐term deep brain stimulation of the subthalamic nucleus promotes cell proliferation and neurogenesis in the subventricular zone that are reduced in Parkinson's disease. Taken together, our results also provide a detailed characterization of the cellular composition of the adult human subventricular zone and caudate nucleus in normal condition and in Parkinson's and Huntington's diseases and demonstrate the plasticity of these regions in response to neurodegeneration. ANN NEUROL 2025;97:894–906

SignificanceWe introduce a fast Raman spectroscopy (SSRS) system that reduces acquisition time and enhances data quality, providing a breakthrough in SSRS for real-time applications. We demonstrate its utility in differentiating brain tissue regions based on lipid and protein content.AimOur primary goal was to develop a fast SSRS system that enables rapid data acquisition for in vivo applications. We aimed to investigate its effectiveness in differentiating brain tissue types by analyzing lipid and protein content, ultimately enhancing classification accuracy and supporting advancements in medical diagnostics.ApproachWe implemented an optimized circuit and signal processing technique to reduce high-frequency noise and improve signal-to-noise ratio. Brain tissue measurements were validated against staining models, and classification accuracy was tested with principal component analysis (PCA) and support vector machine (SVM).ResultsOur SSRS system captures spectra in 1 s which is significantly faster than similar systems. This rapid method enables real-time monitoring and accurate classification of brain regions based on lipid–protein content, confirmed by neurofilament and Nissl staining correlations (R2=0.75 and 0.55, respectively). Tissue classification showed 80.20% accuracy using spectral intensity at the wavenumbers associated with C–H, CH3, and CH2 vibrations and 81.23% accuracy using PCA-derived features (PC1, PC2, and PC3).ConclusionsThe fast-SSRS system marks a significant advance in Raman spectroscopy, improving speed and data quality. Our setup captures finer spectral details, facilitating reliable differentiation of tissue types, as verified by staining methods and PCA. This method shows promise for real-time tissue analysis and medical diagnostics, outperforming traditional Raman techniques in speed and data throughput.