271st ENMC international workshop: Towards a unifying effort to fight Kennedy's disease. 20-22 October 2023, Hoofddorp, Netherlands.

The workshop held in the Netherlands from October 20-22, 2023, united 27 scientists from academia, healthcare, and industry representing 11 countries, alongside four patient and charity representatives. Focused on Kennedy's Disease (KD), also known as spinal and bulbar muscular atrophy (SBMA), the workshop aimed to consolidate knowledge, align on clinical trial designs, and promote participative medicine for effective treatments. Discussions emphasized KD's molecular mechanisms, highlighting its status as a neuromuscular disorder with motor neuron degeneration.

PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons.

Dipeptide repeat proteins are a major pathogenic feature of C9orf72 amyotrophic lateral sclerosis (C9ALS)/frontotemporal dementia (FTD) pathology, but their physiological impact has yet to be fully determined. Here we generated C9orf72 dipeptide repeat knock-in mouse models characterized by expression of 400 codon-optimized polyGR or polyPR repeats, and heterozygous C9orf72 reduction. (GR)400 and (PR)400 knock-in mice recapitulate key features of C9ALS/FTD, including cortical neuronal hyperexcitability, age-dependent spinal motor neuron loss and progressive motor dysfunction.

An optogenetic cell therapy to restore control of target muscles in an aggressive mouse model of amyotrophic lateral sclerosis.

Breakdown of neuromuscular junctions (NMJs) is an early pathological hallmark of amyotrophic lateral sclerosis (ALS) that blocks neuromuscular transmission, leading to muscle weakness, paralysis and, ultimately, premature death. Currently, no therapies exist that can prevent progressive motor neuron degeneration, muscle denervation, or paralysis in ALS. Here, we report important advances in the development of an optogenetic, neural replacement strategy that can effectively restore innervation of severely affected skeletal muscles in the aggressive SOD1 mouse model of ALS, thus providing an interface to selectively control the function of targeted muscles using optical stimulation.

The cholesterol depleting agent, (2-Hydroxypropyl)-ß-cyclodextrin, does not affect disease progression in SOD1 mice.

Previously, we demonstrated that Amyloid Precursor Protein (APP) contributes to pathology in the SOD1 mouse model of ALS and that genetic ablation of APP in SOD1 mice significantly improved multiple disease parameters, including muscle innervation and motor neuron survival. We also observed elevated levels of potentially neurotoxic Aß peptides that have been implicated in Alzheimer's Disease (AD) pathogenesis, within motor neurons and astrocytes in SOD1 mice. More recently, it has been shown that blocking Aß production improves outcome measures in SOD1 mice.

Opinion: more mouse models and more translation needed for ALS.

Amyotrophic lateral sclerosis is a complex disorder most of which is 'sporadic' of unknown origin but approximately 10% is familial, arising from single mutations in any of more than 30 genes. Thus, there are more than 30 familial ALS subtypes, with different, often unknown, molecular pathologies leading to a complex constellation of clinical phenotypes. We have mouse models for many genetic forms of the disorder, but these do not, on their own, necessarily show us the key pathological pathways at work in human patients.

Microglial Expression of the Wnt Signaling Modulator Differs between Human Alzheimer's Disease Brains and Mouse Neurodegeneration Models.

Wnt signaling is crucial for synapse and cognitive function. Indeed, deficient Wnt signaling is causally related to increased expression of an endogenous negative Wnt regulator, and synapse loss, both of which likely contribute to cognitive decline in Alzheimer's disease (AD). Increasingly, AD research efforts have probed the neuroinflammatory role of microglia, the resident immune cells of the CNS, which have furthermore been shown to be modulated by Wnt signaling.

A Fully Implantable Opto-Electro Closed-Loop Neural Interface for Motor Neuron Disease Studies.

This paper presents a fully implantable closed-loop device for use in freely moving rodents to investigate new treatments for motor neuron disease. The 0.18 μm CMOS integrated circuit comprises 4 stimulators, each featuring 16 channels for optical and electrical stimulation using arbitrary current waveforms at frequencies from 1.

Excitability properties of mouse and human skeletal muscle fibres compared by muscle velocity recovery cycles.

Mouse models of skeletal muscle channelopathies are not phenocopies of human disease. In some cases (e.g.

Ageing contributes to phenotype transition in a mouse model of periodic paralysis.

Background: Periodic paralysis (PP) is a rare genetic disorder in which ion channel mutation causes episodic paralysis in association with hyper- or hypokalaemia. An unexplained but consistent feature of PP is that a phenotype transition occurs around the age of 40, in which the severity of potassium-induced muscle weakness declines but onset of fixed, progressive weakness is reported. This phenotype transition coincides with the age at which muscle mass and optimal motor function start to decline in healthy individuals.

Enhanced Expression of TRAP1 Protects Mitochondrial Function in Motor Neurons under Conditions of Oxidative Stress.

TNF-receptor associated protein (TRAP1) is a cytoprotective mitochondrial-specific member of the Hsp90 heat shock protein family of protein chaperones that has been shown to antagonise mitochondrial apoptosis and oxidative stress, regulate the mitochondrial permeability transition pore and control protein folding in mitochondria. Here we show that overexpression of TRAP1 protects motor neurons from mitochondrial dysfunction and death induced by exposure to oxidative stress conditions modelling amyotrophic lateral sclerosis (ALS). ALS is a fatal neurodegenerative disease in which motor neurons degenerate, leading to muscle weakness and atrophy and death, typically within 3 years of diagnosis.

Astrocytes display cell autonomous and diverse early reactive states in familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a rapidly progressive and fatal disease. Although astrocytes are increasingly recognized contributors to the underlying pathogenesis, the cellular autonomy and uniformity of astrocyte reactive transformation in different genetic forms of amyotrophic lateral sclerosis remain unresolved. Here we systematically examine these issues by using highly enriched and human induced pluripotent stem cell-derived astrocytes from patients with VCP and SOD1 mutations.

Circulating miR-181 is a prognostic biomarker for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a relentless neurodegenerative disease of the human motor neuron system, where variability in progression rate limits clinical trial efficacy. Therefore, better prognostication will facilitate therapeutic progress. In this study, we investigated the potential of plasma cell-free microRNAs (miRNAs) as ALS prognostication biomarkers in 252 patients with detailed clinical phenotyping.

Regional Differences in Heat Shock Protein 25 Expression in Brain and Spinal Cord Astrocytes of Wild-Type and SOD1 Mice.

Heterogeneity of glia in different CNS regions may contribute to the selective vulnerability of neuronal populations in neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS). Here, we explored regional variations in the expression of heat shock protein 25 in glia under conditions of acute and chronic stress. Hsp27 (Hsp27; murine orthologue: Hsp25) fulfils a number of cytoprotective functions and may therefore be a possible therapeutic target in ALS.

The altered expression of neurofilament in mouse models and patients with spinal muscular atrophy.

Objectives: To investigate the levels of neurofilaments (NFs) in transgenic mice and patients with spinal muscular atrophy (SMA), and to evaluate their efficacy as a biomarker in SMA.

Methods: The levels of NF mRNA transcripts were measured by quantitative real-time PCR in spinal cord from SMA mice. Blood levels of NF heavy chain (NfH) from mice and patients were measured by an in-house ELISA method.

Automated and unbiased discrimination of ALS from control tissue at single cell resolution.

Histopathological analysis of tissue sections is invaluable in neurodegeneration research. However, cell-to-cell variation in both the presence and severity of a given phenotype is a key limitation of this approach, reducing the signal to noise ratio and leaving unresolved the potential of single-cell scoring for a given disease attribute. Here, we tested different machine learning methods to analyse high-content microscopy measurements of hundreds of motor neurons (MNs) from amyotrophic lateral sclerosis (ALS) post-mortem tissue sections.

Focus on the heterogeneity of amyotrophic lateral sclerosis.

The clinical manifestations of amyotrophic lateral sclerosis (ALS) are variable in terms of age at disease onset, site of onset, progression of symptoms, motor neuron involvement, and the occurrence of cognitive and behavioral changes. Genetic background is a key determinant of the ALS phenotype. The mortality of the disease also varies with the ancestral origin of the affected population and environmental factors are likely to be associated with ALS at least within some cohorts.

Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification.

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis.

IGF1R regulates retrograde axonal transport of signalling endosomes in motor neurons.

Signalling endosomes are essential for trafficking of activated ligand-receptor complexes and their distal signalling, ultimately leading to neuronal survival. Although deficits in signalling endosome transport have been linked to neurodegeneration, our understanding of the mechanisms controlling this process remains incomplete. Here, we describe a new modulator of signalling endosome trafficking, the insulin-like growth factor 1 receptor (IGF1R).