2020 Research

Wide range of reduced penetrance alleles in spinal and bulbar muscular atrophy: a model based approach

Our analysis reveals an unexpectedly high frequency of expanded SBMA-associated alleles, with (CAG)n ≥35 present in 107/100,000 and (CAG)n ≥38 present in 27/100,000 of the general population. We argue against the cut-off model for the penetrance of SBMA and suggest that penetrance gradually increases from 35 to approximately 46 repeats, above which it reaches a plateau approaching maximum value. Therefore, asymptomatic men of the general population with no/ unknown SBMA family history are free of risk when carrying (CAG)n ≤34, are at intermediate but increasing risk for developing SBMA (with greater risk for longer alleles) when carrying (CAG)n ≈35–46 and have close to 100% risk of developing the disease when carrying (CAG)n ≥47. To read the article, click here.


Sonic Hedgehog-Gli1 Signaling and Cellular Retinoic Acid Binding Protein 1 Gene Regulation in Motor Neuron Differentiation and Diseases

We employed the same strategy to engineer healthy vs. degenerated MN1 cells to model SBMA neurons [22]. MN1 cells containing AR-24Q (control) remain healthy, whereas MN1 cells containing the diseased version, AR-65Q, become degenerated in cultures As shown in Figure 2b, the diseased SBMA/MN1 neurons, AR-65Q, also have a dramatically reduced CRABP1 level, as compared to the healthy control, AR-24Q. These results, in two motor neuron disease models, consistently show that Crabp1 gene activity is positively correlated with a healthy state in motor neurons, whereas down regulation of the Crabp1 gene is correlated with degeneration in motor neurons, such as those in ALS and SBMA. To read the article, click here.


Arginine is a disease modifier for polyQ disease models that stabilizes polyQ protein conformation

In this study, we identified arginine as a potent polyQ aggregation inhibitor that acts by inhibiting the formation of misfolded and oligomeric toxic protein species before the formation of insoluble aggregates. We also confirmed its therapeutic effects on neurological symptoms and protein aggregation pathology using two different animal models of polyQ diseases. In addition, we showed that arginine may exert a therapeutic effect on the dendritic arborization of the Purkinje cell in the cerebellum. To read the article, click here.


Muscle BDNF: A Potential Therapeutic Target for Kennedy’s Disease

Novel to this study, the authors developed a 97Q mouse with Cre-dependent overexpression of BDNF (97Q/BDNF) specifically in muscle. This resulted in significant increases in muscle-specific BDNF expression by 150-fold in the fast-twitch tibialis anterior (TA) and 45-fold in the slow-twitch soleus. The hang test, used to determine disease progression, demonstrates neuromuscular impairment and motor coordination in mouse models by measuring how long a mouse can hold their bodyweight using an overhanging bar. In the current study, disease onset was defined as a hang time < 120 seconds for two consecutive days and a hang-time < 30 seconds represented disease end-stage. Overexpression of BDNF was found to significantly increase time to disease onset, endstage and further, doubled survival time. To read the article, click here.


Cell-Clearing Systems Bridging Repeat Expansion Proteotoxicity and Neuromuscular Junction Alterations in ALS and SBMA

The coordinated activities of autophagy and the ubiquitin proteasome system (UPS) are key to preventing the aggregation and toxicity of misfold-prone proteins which manifest in a number of neurodegenerative disorders. These include proteins which are encoded by genes containing nucleotide repeat expansions. In the present review we focus on the overlapping role of autophagy and the UPS in repeat expansion proteotoxicity associated with chromosome 9 open reading frame 72 (C9ORF72) and androgen receptor (AR) genes, which are implicated in two motor neuron disorders, amyotrophic lateral sclerosis (ALS) and spinal-bulbar muscular atrophy (SBMA), respectively. At baseline, both C9ORF72 and AR regulate autophagy, while their aberrantly-expanded isoforms may lead to a failure in both autophagy and the UPS, further promoting protein aggregation and toxicity within motor neurons and skeletal muscles. Besides proteotoxicity, autophagy and UPS alterations are also implicated in neuromuscular junction (NMJ) alterations, which occur early in both ALS and SBMA. In fact, autophagy and the UPS intermingle with endocytic/secretory pathways to regulate axonal homeostasis and neurotransmission by interacting with key proteins which operate at the NMJ, such as agrin, acetylcholine receptors (AChRs), and adrenergic beta2 receptors (B2-ARs). Thus, alterations of autophagy and the UPS configure as a common hallmark in both ALS and SBMA disease progression. To read the article, click here.


Muscle BDNF improves synaptic and contractile muscle strength in Kennedy's disease mice in a muscle‐type specific manner.

We report that a muscle‐derived neurotrophic factor, BDNF, rescues synaptic and muscle function in a muscle‐type specific manner in mice modelling Kennedy's disease (KD). We also find that BDNF rescues select molecular mechanisms in slow and fast muscle that may underlie the improved cellular function. We also report for the first time that expression of BDNF, but not other members of the neurotrophin family, is perturbed in muscle from patients with KD. To read the article, click here.


MEF2 impairment underlies skeletal muscle atrophy in polyglutamine disease

We find no evidence to suggest dysfunction of signaling pathways that trigger muscle hypertrophy or impairment of the muscle stem cell niche. Instead, we find that skeletal muscle atrophy is characterized by diminished function of the transcriptional regulator Myocyte Enhancer Factor 2 (MEF2), a regulator of myofiber homeostasis. Decreased expression of MEF2 target genes is age- and glutamine tract length-dependent, occurs due to polyQ AR proteotoxicity, and is associated with sequestration of MEF2 into intranuclear inclusions in muscle. To read the article, click here.


Enhanced Clearance of Neurotoxic Misfolded Proteins by the Natural Compound Berberine and Its Derivatives

We tested the natural alkaloid berberine (BBR) and some derivatives for their capability to enhance misfolded protein clearance in cell models of NDs, evaluating which degradative pathway mediates their action. Results: We found that both BBR and its semisynthetic derivatives promote degradation of mutant androgen receptor (ARpolyQ) causative of spinal and bulbar muscular atrophy, acting mainly via proteasome and preventing ARpolyQ aggregation. To read the article, click here.


Deterioration of muscle force and contractile characteristics are early pathological events in spinal and bulbar muscular atrophy mice

To fully characterise the role of muscle in SBMA, we undertook a longitudinal physiological and histological characterisation of disease progression in the AR100 mouse model of SBMA. Our results show that the disease first manifests in skeletal muscle, prior to any motor neuron degeneration, which only occurs in late stage disease. These findings reveal alterations in muscle function, including reduced muscle force and changes in contractile characteristics, are early pathological events in SBMA mice and suggest that muscle-targeted therapeutics may be effective in SBMA. To read the article. Click here.


Unveiling synapse pathology in spinal bulbar muscular atrophy by genome-wide transcriptome analysis of purified motor neurons derived from disease specific iPSCs

Although ligand (testosterone)-dependent mutant AR aggregation has been shown to play important roles in motor neuronal degeneration by the analyses of transgenic mice models and in vitro cell culture models, the underlying disease mechanisms remain to be fully elucidated because of the discrepancy between model mice and SBMA patients. ...we established disease specific iPSCs from four SBMA patients, and differentiated them into spinal motor neurons. The results revealed the involvement of the pathology associated with synapses, epigenetics, and endoplasmic reticulum (ER) in SBMA. To read the article. Click here.


Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism

 We generated new mouse models of SBMA for constitutive and inducible expression of mutant AR and performed biochemical, histological and functional analyses of phenotype. We show that polyQ-expanded AR causes motor dysfunction, premature death, IIb-to-IIa/IIx fiber-type change, glycolytic-to-oxidative fiber-type switching, upregulation of atrogenes and autophagy genes and mitochondrial dysfunction in skeletal muscle, together with signs of muscle denervation at late stage of disease.

Finally, we found that two-week induction of expression of polyQ-expanded AR in adult mice was sufficient to cause premature death, body weight loss and muscle atrophy, but not aggregation, metabolic alterations, motor coordination and fiber-type switch, indicating that expression of the disease protein in the adulthood is sufficient to recapitulate several, but not all SBMA manifestations in mice. These results imply that chronic expression of polyQ-expanded AR, i.e. during development and prepuberty, is key to induce the full SBMA muscle pathology observed in patients. To read the article. Click here.