Cortical neuronal hyperexcitability and synaptic changes in <i>SGCE</i> mutation-positive myoclonus dystonia

Sperandeo, Alessandra; Tamburini, Claudia; Noakes, Zoe; Fuente, Daniel C. De La; Keefe, Francesca; Petter, Olena; Plumbly, William; Clifton, Nicholas E.; Li, Meng; Peall, Kathryn J.

doi:10.1093/brain/awac365

Cited by 10 publications

(5 citation statements)

References 91 publications

(112 reference statements)

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“…This finding is in line with recent observations describing an increased number of branches and longer branch lengths in dendrites in cortical cells in subjects with SGCE -mutation. 30 Indeed, greater microstructural complexity in the entanglement of cytoplasmic protrusions from neurons (e.g. axons and dendrites) and glial cells in the extracellular space may constrain water diffusivity, 58-60 consistent with the decreased MD we observed in DYT- SGCE patients.…”

Section: Discussionsupporting

confidence: 69%

Association of abnormal explicit sense of agency with cerebellar impairment in myoclonus-dystonia

Tarrano,

Galléa,

Delorme

et al. 2024

Brain Communications

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Non-motor aspects in dystonia are now well recognized. The sense of agency, which refers to the experience of controlling one's own actions, has been scarcely studied in dystonia, even though its disturbances can contribute to movement disorders. Among various brain structures, the cerebral cortex, the cerebellum, and the basal ganglia are involved in shaping the sense of agency. In myoclonus-dystonia, resulting from a dysfunction of the motor network, an altered sense of agency may contribute to the clinical phenotype of the condition. In this study, we compared the explicit and implicit sense of agency in patients with myoclonus-dystonia caused by a pathogenic variant of SGCE (DYT-SGCE) and control participants. We utilized behavioral tasks to assess the sense of agency and performed neuroimaging analyses, including structural, resting-state functional connectivity, and dynamic causal modeling, to explore the relevant brain regions involved in the sense of agency. Additionally, we examined the relationship between behavioral performance, symptom severity, and neuroimaging findings. We compared 19 patients with DYT-SGCE and 24 healthy volunteers. Our findings revealed that patients with myoclonus-dystonia exhibited a specific impairment in explicit sense of agency, particularly when implicit motor learning was involved. However, their implicit sense of agency remained intact. These patients also displayed grey matter abnormalities in the motor cerebellum, as well as increased functional connectivity between the cerebellum and pre-supplementary motor area (pre-SMA). Dynamic causal modeling analysis further identified reduced inhibitory effects of the cerebellum on the pre-SMA, decreased excitatory effects of the pre-SMA on the cerebellum, and increased self-inhibition within the pre-SMA. Importantly, both cerebellar grey matter alterations and functional connectivity abnormalities between the cerebellum and pre-SMA were found to correlate with explicit sense of agency impairment. Increased self-inhibition within the pre-SMA was associated with less severe myoclonus symptoms. These findings highlight the disruption of higher-level cognitive processes in patients with myoclonus-dystonia, further expanding the spectrum of neurological and psychiatric dysfunction already identified in this disorder.

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Section: Discussionsupporting

confidence: 69%

Association of abnormal explicit sense of agency with cerebellar impairment in myoclonus-dystonia

Tarrano,

Galléa,

Delorme

et al. 2024

Brain Communications

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“…In brain development, all cortical glutamatergic neurons originate from the embryonic dorsal telencephalon [ 151 ], which is patterned by WNTs and BMPs that are derived from the cortical hem [ 152 , 153 ]. Early dorsal forebrain primordium co-express Pax6 and Otx1/2, and over time, these cells differentiated into cortical glutamatergic neurons, displaying unipolar and pyramidal morphology, and expressing TBR1, CTIP2, and vesicular glutamate transporters [ 154 , 155 ]. Glutamatergic neurogenesis is also present in adult neurogenic niches, SVZ and SGZ [ 156 , 157 ].…”

Section: The Directional Differentiation Of Nscs From Different Sourc...mentioning

confidence: 99%

Directional induction of neural stem cells, a new therapy for neurodegenerative diseases and ischemic stroke

et al. 2023

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Due to the limited capacity of the adult mammalian brain to self-repair and regenerate, neurological diseases, especially neurodegenerative disorders and stroke, characterized by irreversible cellular damage are often considered as refractory diseases. Neural stem cells (NSCs) play a unique role in the treatment of neurological diseases for their abilities to self-renew and form different neural lineage cells, such as neurons and glial cells. With the increasing understanding of neurodevelopment and advances in stem cell technology, NSCs can be obtained from different sources and directed to differentiate into a specific neural lineage cell phenotype purposefully, making it possible to replace specific cells lost in some neurological diseases, which provides new approaches to treat neurodegenerative diseases as well as stroke. In this review, we outline the advances in generating several neuronal lineage subtypes from different sources of NSCs. We further summarize the therapeutic effects and possible therapeutic mechanisms of these fated specific NSCs in neurological disease models, with special emphasis on Parkinson’s disease and ischemic stroke. Finally, from the perspective of clinical translation, we compare the strengths and weaknesses of different sources of NSCs and different methods of directed differentiation, and propose future research directions for directed differentiation of NSCs in regenerative medicine.

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“…Axonal regeneration and synaptogenesis are key factors in neuronal network reconstruction and neurological function recovery after spinal cord injury. Among them, Nf-200 and Synaptophysin are key markers of axonal regeneration and synapse formation, respectively [43,44]. To test whether the injured spinal cord with knockdown of Ski could exhibit stronger axonal regeneration and synaptogenesis, the expression levels of Nf-200 and Synaptophysin in each group at 1, 2, 4, 6, and 8 w after spinal cord injury were examined by using Western Blotting.…”

Section: Ski Knockdown Promotes Axonal Regeneration and Synapse Forma...mentioning

confidence: 99%

Lentivirus-mediated knockdown of Ski inhibits glial scar formation and promotes axonal regeneration and functional recovery after spinal cord injury in rats

Wang

Ran

et al. 2023

Preprint

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The glial scar that forms at the site of injury after spinal cord injury (SCI) is an important physical and biochemical barrier that prevents axonal regeneration and thus delays functional recovery. Ski is a multifunctional transcriptional co-regulator that is involved in a wide range of physiological and pathological processes in humans. Previous studies by our group found that Ski is significantly upregulated in the spinal cord after in vivo injury and in astrocytes after in vitro activation, suggesting that Ski may be a novel molecule regulating astrocyte activation after spinal cord injury. Further studies revealed that knockdown or overexpression intervention of Ski expression could significantly affect the proliferation and migration of activated astrocytes. To further verify the effect of knockdown of Ski expression in vivo on glial scar formation and functional recovery after spinal cord injury, we prepared a rat spinal cord injury model using Allen's percussion method and used lentivirus as a vector to mediate the downregulation of Ski in the injured spinal cord. The results showed that knockdown of Ski expression after spinal cord injury significantly inhibited the expression of Glial Fibrillary Acidic Protein (Gfap) and Vimentin, the hallmark molecules of glial scar, and increased the expression of Neurofilament-200 (Nf-200), a key molecule for axonal regeneration, and Synaptophysin, a key molecule for synapse formation. In addition, knockdown of Ski after spinal cord injury also promoted the recovery of motor function. Taken together, these results demonstrate that Ski is an important regulator of glial scar formation at the injury site and promotes axonal regeneration and synapse formation after spinal cord injury, and is a potential target for targeted therapy after spinal cord injury.

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Cortical neuronal hyperexcitability and synaptic changes in SGCE mutation-positive myoclonus dystonia

Cited by 10 publications

References 91 publications

Association of abnormal explicit sense of agency with cerebellar impairment in myoclonus-dystonia

Association of abnormal explicit sense of agency with cerebellar impairment in myoclonus-dystonia

Directional induction of neural stem cells, a new therapy for neurodegenerative diseases and ischemic stroke

Lentivirus-mediated knockdown of Ski inhibits glial scar formation and promotes axonal regeneration and functional recovery after spinal cord injury in rats

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