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Mutation in Wdr45 leads to early motor dysfunction and widespread aberrant axon terminals in a beta-propeller protein associated neurodegeneration (BPAN) patient-inspired mouse model

ABSTRACT: Mutation in Wdr45 leads to early motor dysfunction and widespread aberrant axon terminals in a beta-propeller protein associated neurodegeneration (BPAN) patient-inspired mouse model

PROVIDER: PRJNA1217880 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32190448_1.fastq.gz	Fastqsanger.gz
	SRR32190448_2.fastq.gz	Fastqsanger.gz
	SRR32190449_1.fastq.gz	Fastqsanger.gz
	SRR32190449_2.fastq.gz	Fastqsanger.gz
	SRR32190450_1.fastq.gz	Fastqsanger.gz

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Mutation in Wdr45 leads to early motor dysfunction and widespread aberrant axon terminals in a beta-propeller protein associated neurodegeneration (BPAN) patient-inspired mouse model

Project description:Beta-propeller Protein Associated Neurodegeneration (BPAN) is a devastating neurodevelopmental and neurodegenerative disease linked to variants in WDR45. Currently, there is no cure or disease altering treatment for this disease. This is, in part, due to a lack of insight into early phenotypes of BPAN progression and WDR45’s role in establishing and maintaining neurological function. Here we generated and characterized a mouse model bearing a c52C>T BPAN patient variant in Wdr45. We show this mutation ablates WDR45 protein expression and alters autophagy in the brain. Behavioral analysis of these mice revealed characteristic signs of BPAN including cognitive impairment, hyperactivity, and motor decline. We show these behaviors coincide with widespread glial activation and development of axonal spheroids in multiple neuron subclasses throughout the brain. Several lines of evidence suggest these spheroids arise from axon terminals. Transcriptomic analysis uncovered multiple disrupted pathways in the cortex including genes associated with synapses, neurites, endosomes, endoplasmic reticulum, and ferroptosis. This is supported by accumulation of the iron regulating transferrin receptor 1 (TFRC) and the endoplasmic reticulum resident calreticulin (CALR) in the cortex as these animals age. CALR forms spheroid structures similar to the axonal spheroids seen in these animals. Taken together, our data suggest that WDR45 is necessary for healthy brain function and maintenance of axon terminals. This model opens the door to therapeutics targeting BPAN and further exploration of the role of WDR45 in neuronal function.

2025-02-05 | GSE288499 | GEO

Mutation in <i>Wdr45</i> leads to early motor dysfunction and widespread aberrant axon terminals in a beta-propeller protein associated neurodegeneration (BPAN) patient-inspired mouse model.

Project description:Beta-propeller Protein Associated Neurodegeneration (BPAN) is a devastating neurodevelopmental and neurodegenerative disease linked to variants in WDR45. Currently, there is no cure or disease altering treatment for this disease. This is, in part, due to a lack of insight into early phenotypes of BPAN progression and WDR45's role in establishing and maintaining neurological function. Here we generated and characterized a mouse model bearing a c52C > T BPAN patient variant in Wdr45. We show this mutation ablates WDR45 protein expression and alters autophagy in the brain. Behavioral analysis of these mice revealed characteristic signs of BPAN including cognitive impairment, hyperactivity, and motor decline. We show these behaviors coincide with widespread glial activation and early development of axonal spheroids in multiple neuron subclasses throughout the brain. Several lines of evidence suggest these spheroids arise from axon terminals. Transcriptomic analysis uncovered multiple disrupted pathways in the cortex including genes associated with synapses, neurites, endosomes, endoplasmic reticulum, and ferroptosis. This is supported by accumulation of the iron regulating transferrin receptor 1 (TFRC) and the endoplasmic reticulum resident calreticulin (CALR) in the cortex as these animals age. CALR forms spheroid structures similar to the axonal spheroids seen in these animals. Taken together, our data suggest that WDR45 is necessary for healthy brain function and maintenance of axon terminals. This model opens the door to therapeutics targeting BPAN and further exploration of the role of WDR45 in neuronal function.

| S-EPMC11907653 | biostudies-literature

The serotonin transporter is a regulator of neurodegeneration and axon regeneration after retinal injury

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SEMA3B switches axon-axon to axon-glia interactions required for unmyelinated axon envelopment and integrity

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SEMA3B switches axon-axon to axon-glia interactions required for unmyelinated axon envelopment and integrity

Project description:During peripheral nerve (PN) development, unmyelinated axons (nmAs) initially form tight fascicles before being separated and enveloped by non-myelinating Schwann cells (nmSCs), which are essential for maintaining nmA integrity. The mechanism underlying this transition from axon-axon to axon-glia interactions remains unclear. Here, we found that inactivating nmSC-derived SEMA3B or its axonal receptor components in mice led to incomplete nmA separation and envelopment by nmSCs, leading to nmA dysfunction and inducing hyperalgesia and allodynia. Conversely, increasing SEMA3B levels in nmSCs accelerated nmA separation and envelopment. SEMA3B transiently promoted nmA defasciculation accompanied by cell adhesion molecule (CAM) endocytosis, thus facilitating subsequent CAM-mediated nmA-mSC association. Restoring SEMA3B expression post-PN injury promoted nmA-nmSC re-association and alleviated hyperalgesia and allodynia. We propose that SEMA3B-induced CAM turnover facilitates the switch from axon-axon to axon-glia interactions, promoting nmA envelopment by nmSCs, which may be exploited to alleviate PN injury-induced pain by accelerating the restoration of nmA integrity.

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The serotonin transporter is a regulator of neurodegeneration and axon regeneration after retinal injury

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2020-07-11 | GSE153812 | GEO

Genetically perturbed myelin as a risk factor for neuroinflammation-driven axon degeneration

Project description:Axon degeneration and neurological dysfunction in myelin diseases is often attributed to loss of myelin. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal damage. We have previously shown in mice that distinct defects in the proteolipid protein 1 gene result in axonal damage which is largely driven by cytotoxic T cells targeting myelinating oligodendrocytes. Here we show in these mutants that persistent ensheathment with perturbed myelin poses a risk for axon degeneration, neuron loss, and behavioral decline. We demonstrate that CD8+ T cell-driven axonal damage is less likely to progress towards degeneration when axons are efficiently demyelinated by activated microglia. Mechanistically, we show that cytotoxic T cell effector molecules induce aberrant cytoskeletal plasticity within myelinating glial processes and constriction of axons at paranodal domains. Our study identifies detrimental axon-glia interactions which promote neurodegeneration and possible therapeutic targets for disorders associated with myelin defects and neuroinflammation.

2023-09-29 | GSE224032 | GEO

Axon-enriched lincRNA ALAE is required for axon elongation via regulating local mRNA translation

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Pathophysiology of microglial-driven neurodegeneration in Histiocytosis

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