Neurodevelopmental Clues to Neurodegeneration

Schor, Nina F.; Bianchi, Diana W.

doi:10.1016/j.pediatrneurol.2021.07.012

Cited by 20 publications

(10 citation statements)

References 88 publications

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“…For instance, proteins, such as Aβ, MAPT/tau, Rac1, progranulin, huntingtin, PINK and parkin, frequently implicated in Alzheimer’s disease, Parkinson’s disease and Huntington’s diseases are important for nervous system development. 41 A wide range of multisystem genetic disorders could present with a biphasic course where a complex neurological phenotype gradually evolves on the background of a pre-existing neurodevelopmental disorder. 42 , 43 Therefore, we propose a likely clinical continuum associated with ACBD6 -related disease, characterized by a combination of neurodevelopmental abnormalities and neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders

Kaiyrzhanov,

Rad,

Lin

et al. 2023

Brain

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The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins, and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Utilizing exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with YnMyr chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), with ages ranging from 1 to 50 years old, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%), and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%), and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%), and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each), as well as hypertrophy of the clava (24%) were common neuroimaging findings. acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism, and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localisation and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-Myristoylation was similarly affected in acbd6-deficient zebrafish and Xenopus tropicalis models, including Fus, Marcks, and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders.

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Section: Discussionmentioning

confidence: 99%

Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders

Kaiyrzhanov,

Rad,

Lin

et al. 2023

Brain

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“…A growing amount of evidence suggests altered neurodevelopment due to loss of function of important genes for brain development like huntingtin is an important feature of disease pathogenesis in polyglutamine diseases and other neurodegenerative disorders. [43][44][45][46][47][48][49][100][101][102] Our study suggests that, in addition to LOF effects, GOF effects may also play a role in neurodevelopmental defects observed in polyglutamine disease.…”

Section: Implications For and Potential Therapeutic Avenues In Neurod...mentioning

confidence: 99%

Dendrite injury, but not axon injury, triggers neuroprotection in Drosophila models of neurodegenerative disease

Prange,

Bhakta,

Sysoeva

et al. 2024

Preprint

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Dendrite defects and loss are early cellular alterations observed across neurodegenerative diseases that play a role in early disease pathogenesis. Dendrite degeneration can be modeled by expressing pathogenic polyglutamine disease transgenes in Drosophila neurons in vivo. Here, we show that we can protect against dendrite loss in neurons modeling neurodegenerative polyglutamine diseases through injury to a single primary dendrite branch. We find that this neuroprotection is specific to injury-induced activation of dendrite regeneration: neither injury to the axon nor injury just to surrounding tissues induces this response. We show that the mechanism of this regenerative response is stabilization of the actin (but not microtubule) cytoskeleton. We also demonstrate that this regenerative response may extend to other neurodegenerative diseases. Together, we provide evidence that activating dendrite regeneration pathways has the potential to slow or even reverse dendrite loss in neurodegenerative disease.

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“…It is well known that alterations in brain maturation and plasticity are linked to the emergence of neurological disorders [112][113][114][115][116][117]. In particular, schizophrenia and psychosis spectrum disorders are associated with an impacted timeline of brain maturation [29,118].…”

Section: Role Of Brain Plasticity and Immaturity In Psychiatric And Neurological Disordersmentioning

confidence: 99%

Brain Plasticity in Humans and Model Systems: Advances, Challenges, and Future Directions

Bonfanti

Charvet

2021

IJMS

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Plasticity, and in particular, neurogenesis, is a promising target to treat and prevent a wide variety of diseases (e.g., epilepsy, stroke, dementia). There are different types of plasticity, which vary with age, brain region, and species. These observations stress the importance of defining plasticity along temporal and spatial dimensions. We review recent studies focused on brain plasticity across the lifespan and in different species. One main theme to emerge from this work is that plasticity declines with age but that we have yet to map these different forms of plasticity across species. As part of this effort, we discuss our recent progress aimed to identify corresponding ages across species, and how this information can be used to map temporal variation in plasticity from model systems to humans.

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Neurodevelopmental Clues to Neurodegeneration

Cited by 20 publications

References 88 publications

Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders

Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders

Dendrite injury, but not axon injury, triggers neuroprotection in Drosophila models of neurodegenerative disease

Brain Plasticity in Humans and Model Systems: Advances, Challenges, and Future Directions

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