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Neurofilament accumulations in Amyotrophic Lateral Sclerosis patients’ motor neurons impair structural axonal initial segment integrity

ABSTRACT: Neurofilament accumulations in Amyotrophic Lateral Sclerosis patients’ motor neurons impair structural axonal initial segment integrity

PROVIDER: PRJNA824791 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18685800_1.fastq.gz	Fastqsanger.gz
	SRR18685800_2.fastq.gz	Fastqsanger.gz
	SRR18685801_1.fastq.gz	Fastqsanger.gz
	SRR18685801_2.fastq.gz	Fastqsanger.gz
	SRR18685802_1.fastq.gz	Fastqsanger.gz

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Neurofilament accumulations in Amyotrophic Lateral Sclerosis patients’ motor neurons impair structural axonal initial segment integrity

Project description:Neurofilament (NF) accumulation is a pathological hallmark observed in motor neurons (MNs) of patients with Amyotrophic Lateral Sclerosis (ALS) and levels of NF in fluids is becoming the prime biomarker of ALS progression. However, the underlying mechanisms linking NF accumulations and MN degeneration are not elucidated. Here, we show that integrity of the axonal initial segment (AIS), the region of action potential initiation and of polarized trafficking, is impaired by NF accumulations in human MNs carrying mutations in the two main causal ALS genes: C9ORF72 and SOD1. We show that in mutant MNs derived from induced pluripotent stem cells, both light (NF-L) and phosphorylated heavy chains (pNF-H) accumulated progressively with MN aging and that pNF-H accumulation in the AIS region led to significant structural and molecular alterations. In parallel, ALS MNs acquired altered excitability with aging. Focusing on axonal organization appears as an effective readout for MN cell death and preserving AIS integrity could have important therapeutic implications.

2024-07-03 | GSE200474 | GEO

Neurofilament accumulations in amyotrophic lateral sclerosis patients' motor neurons impair axonal initial segment integrity.

Project description:Amyotrophic lateral sclerosis (ALS) is the most common motor neuron (MN) disease in adults with no curative treatment. Neurofilament (NF) level in patient' fluids have recently emerged as the prime biomarker of ALS disease progression, while NF accumulation in MNs of patients is the oldest and one of the best pathological hallmarks. However, the way NF accumulations could lead to MN degeneration remains unknown. To assess NF accumulations and study the impact on MNs, we compared MNs derived from induced pluripotent stem cells (iPSC) of patients carrying mutations in C9orf72, SOD1 and TARDBP genes, the three main ALS genetic causes. We show that in all mutant MNs, light NF (NF-L) chains rapidly accumulate in MN soma, while the phosphorylated heavy/medium NF (pNF-M/H) chains pile up in axonal proximal regions of only C9orf72 and SOD1 MNs. Excitability abnormalities were also only observed in these latter MNs. We demonstrate that the integrity of the MN axonal initial segment (AIS), the region of action potential initiation and responsible for maintaining axonal integrity, is impaired in the presence of pNF-M/H accumulations in C9orf72 and SOD1 MNs. We establish a strong correlation between these pNF-M/H accumulations, an AIS distal shift, increased axonal calibers and modified repartition of sodium channels. The results expand our understanding of how NF accumulation could dysregulate components of the axonal cytoskeleton and disrupt MN homeostasis. With recent cumulative evidence that AIS alterations are implicated in different brain diseases, preserving AIS integrity could have important therapeutic implications for ALS.

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Drosophila voltage-gated sodium channels are only expressed in active neurons and are localized to distal axonal initial segment-like domains

Project description:In multipolar vertebrate neurons, action potentials (AP) initiate close to the soma, at the axonal initial segment (AIS). Invertebrate neurons are typically unipolar with dendrites integrating directly into the axon. Where APs are initiated in the axons of invertebrate neurons is unclear. Voltage-gated sodium (NaV) channels are a functional hallmark of the AIS in vertebrates. We used an intronic MiMIC to determine the endogenous gene expression and subcellular localization of the sole NaV channel in both male and female Drosophila, para. Despite being the only NaV channel in the fly, we show that only 23 ±1% of neurons in the embryonic and larval CNS express para, while in the adult CNS para is broadly expressed. We generated a single-cell transcriptomic atlas of the whole 3rd instar larval brain to identify para expressing neurons and show that it positively correlates with markers of differentiated, actively firing neurons. Therefore only 23 ±1% of larval neurons may be capable of firing NaV-dependent APs. We then show that Para is enriched in an axonal segment, distal to the site of dendritic integration into the axon, which we named the Distal Axonal Segment (DAS). The DAS is present in multiple neuron classes in both the 3rd instar larval and adult CNS. Whole cell patch clamp electrophysiological recordings of adult CNS fly neurons are consistent with the interpretation that Nav-dependent APs originate in the DAS. Identification of the distal NaV localization in fly neurons will enable more accurate interpretation of electrophysiological recordings in invertebrates.

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Project description:The axon initial segment (AIS) is a specialized neuronal compartment required for action potential generation and neuronal polarity. However, understanding the mechanisms regulating AIS structure and function has been hindered by an incomplete knowledge of its molecular composition. Here, using immuno-proximity biotinylation we further define the AIS proteome and its dynamic changes during neuronal maturation. Among the many AIS proteins identified, we show that SCRIB is highly enriched in the AIS both in vitro and in vivo, and exhibits a periodic architecture like the axonal spectrin-based cytoskeleton. We found that ankyrinG interacts with and recruits SCRIB to the AIS. However, loss of SCRIB has no effect on ankyrinG. This powerful and flexible approach further defines the AIS proteome and provides a rich resource to elucidate the mechanisms regulating AIS structure and function.

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Project description:Sporadic Amyotrophic Lateral Sclerosis Study

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