A review: Management of motor neuron diseases

Motor neuron diseases are a group of chronic sporadic and hereditary neurological disorders characterized by progressive degeneration of motor neurons. These might affect the upper motor neurons, lower motor neurons, or both. The prognosis of the motor neuron disease depends upon the age at onset and the area of the central nervous system affected. Amyotrophic lateral sclerosis (ALS) has been documented to be fatal within three years of onset. This activity focuses on amyotrophic lateral sclerosis as the prototype of MND, which affects both the upper and the lower motor neurons and discusses the role of inter-professional team in the differential diagnosis, evaluation, treatment, and prognostication. It also discusses various other phenotypes of MND with an emphasis on their distinguishing features in requisite detail.

Restoration of the Phenotype of Dedifferentiated Rabbit Chondrocytes by Sesquiterpene Farnesol

Osteoarthritis (OA) is a joint disorder characterized by the progressive degeneration of articular cartilage. The phenotype and metabolism behavior of chondrocytes plays crucial roles in maintaining articular cartilage function. Chondrocytes dedifferentiate and lose their cartilage phenotype after successive subcultures or inflammation and synthesize collagen I and X (COL I and COL X). Farnesol, a sesquiterpene compound, has an anti-inflammatory effect and promotes collagen synthesis. However, its potent restoration effects on differentiated chondrocytes have seldom been evaluated. The presented study investigated farnesol’s effect on phenotype restoration by examining collagen and glycosaminoglycan (GAG) synthesis from dedifferentiated chondrocytes. The results indicated that chondrocytes gradually dedifferentiated through cellular morphology change, reduced expressions of COL II and SOX9, increased the expression of COL X and diminished GAG synthesis during four passages of subcultures. Pure farnesol and hyaluronan-encapsulated farnesol nanoparticles promote COL II synthesis. GAG synthesis significantly increased 2.5-fold after a farnesol treatment of dedifferentiated chondrocytes, indicating the restoration of chondrocyte functions. In addition, farnesol drastically increased the synthesis of COL II (2.5-fold) and GAG (15-fold) on interleukin-1β-induced dedifferentiated chondrocytes. A significant reduction of COL I, COL X and proinflammatory cytokine prostaglandin E2 was observed. In summary, farnesol may serve as a therapeutic agent in OA treatment.

Functional assays of non-canonical splice-site variants in inherited retinal dystrophies genes

Inherited retinal dystrophies are a group of disorders characterized by the progressive degeneration of photoreceptors leading to loss of the visual function and eventually to legal blindness. Although next generation sequencing (NGS) has revolutionized the molecular diagnosis of these diseases, the pathogenicity of some mutations casts doubts. After the screening of 208 patients with a panel of 117 genes, we obtained 383 variants that were analysed in silico with bioinformatic prediction programs. Based on the results of these tools, we selected 15 variants for their functional assessment. Therefore, we carried out minigene assays to unveil whether they could affect the splicing of the corresponding gene. As a whole, seven variants were found to induce aberrant splicing in the following genes: BEST1, CACNA2D4, PRCD, RIMS1, FSCN2, MERTK and MAK. This study shows the efficacy of a workflow, based on the association of the Minimum Allele Frequency, family co-segregation, in silico predictions and in vitro assays to determine the effect of potential splice site variants identified by DNA-based NGS. These findings improve the molecular diagnosis of inherited retinal dystrophies and will allow some patients to benefit from the upcoming gene-based therapeutic strategies.

Analysis of the Biomarkers for Neurodegenerative Diseases in Aged Progranulin Deficient Mice

Neurodegenerative diseases are debilitating impairments that affect millions of people worldwide and are characterized by progressive degeneration of structure and function of the central or peripheral nervous system. Effective biomarkers for neurodegenerative diseases can be used to improve the diagnostic workup in the clinic as well as facilitate the development of effective disease-modifying therapies. Progranulin (PGRN) has been reported to be involved in various neurodegenerative disorders. Hence, in the current study we systematically compared the inflammation and accumulation of typical neurodegenerative disease markers in the brain tissue between PGRN knockout (PGRN KO) and wildtype (WT) mice. We found that PGRN deficiency led to significant neuron loss as well as activation of microglia and astrocytes in aged mice. Several characteristic neurodegenerative markers, including α-synuclein, TAR DNA-binding protein 43 (TDP-43), Tau, and β-amyloid, were all accumulated in the brain of PGRN-deficient mice as compared to WT mice. Moreover, higher aggregation of lipofuscin was observed in the brain tissue of PGRN-deficient mice compared with WT mice. In addition, the autophagy was also defective in the brain of PGRN-deficient mice, indicated by the abnormal expression level of autophagy marker LC3-II. Collectively, comprehensive assays support the idea that PGRN plays an important role during the development of neurodegenerative disease, indicating that PGRN might be a useful biomarker for neurodegenerative diseases in clinical settings.

Proteinopathies as Hallmarks of Impaired Gene Expression, Proteostasis and Mitochondrial Function in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons. As with the majority of neurodegenerative diseases, the pathological hallmarks of ALS involve proteinopathies which lead to the formation of various polyubiquitylated protein aggregates in neurons and glia. ALS is a highly heterogeneous disease, with both familial and sporadic forms arising from the convergence of multiple disease mechanisms, many of which remain elusive. There has been considerable research effort invested into exploring these disease mechanisms and in recent years dysregulation of RNA metabolism and mitochondrial function have emerged as of crucial importance to the onset and development of ALS proteinopathies. Widespread alterations of the RNA metabolism and post-translational processing of proteins lead to the disruption of multiple biological pathways. Abnormal mitochondrial structure, impaired ATP production, dysregulation of energy metabolism and calcium homeostasis as well as apoptosis have been implicated in the neurodegenerative process. Dysfunctional mitochondria further accumulate in ALS motor neurons and reflect a wider failure of cellular quality control systems, including mitophagy and other autophagic processes. Here, we review the evidence for RNA and mitochondrial dysfunction as some of the earliest critical pathophysiological events leading to the development of ALS proteinopathies, explore their relative pathological contributions and their points of convergence with other key disease mechanisms. This review will focus primarily on mutations in genes causing four major types of ALS (C9ORF72, SOD1, TARDBP/TDP-43, and FUS) and in protein homeostasis genes (SQSTM1, OPTN, VCP, and UBQLN2) as well as sporadic forms of the disease. Finally, we will look to the future of ALS research and how an improved understanding of central mechanisms underpinning proteinopathies might inform research directions and have implications for the development of novel therapeutic approaches.

Contingent intramuscular boosting of P2XR7 axis improves motor function in transgenic ALS mice

Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder that leads to progressive degeneration of motor neurons and severe muscle atrophy without effective treatment. Most research on the disease has been focused on studying motor neurons and supporting cells of the central nervous system. Strikingly, the recent observations have suggested that morpho-functional alterations in skeletal muscle precede motor neuron degeneration, bolstering the interest in studying muscle tissue as a potential target for the delivery of therapies. We previously showed that the systemic administration of the P2XR7 agonist, 2′(3′)-O‐(4-benzoylbenzoyl) adenosine 5-triphosphate (BzATP), enhanced the metabolism and promoted the myogenesis of new fibres in the skeletal muscles of SOD1G93A mice. Here we further corroborated this evidence showing that intramuscular administration of BzATP improved the motor performance of ALS mice by enhancing satellite cells and the muscle pro-regenerative activity of infiltrating macrophages. The preservation of the skeletal muscle retrogradely propagated along with the motor unit, suggesting that backward signalling from the muscle could impinge on motor neuron death. In addition to providing the basis for a suitable adjunct multisystem therapeutic approach in ALS, these data point out that the muscle should be at the centre of ALS research as a target tissue to address novel therapies in combination with those oriented to the CNS.

Translational readthrough as a potential therapeutic for AIPL1-associated Leber Congenital Amaurosis in a patient-derived iPSC-retinal organoid model

Leber Congenital Amaurosis type 4 (LCA4), caused by AIPL1 mutations, is characterised by severe sight impairment in infancy and rapidly progressive degeneration of photoreceptor cells. We generated retinal organoids using induced pluripotent stem cells (iPSCs) from renal epithelial cells obtained from four children with AIPL1 nonsense mutations. iPSC-derived photoreceptors exhibited the molecular hallmarks of LCA4, including undetectable AIPL1 and rod cGMP phosphodiesterase (PDE6) compared to control or CRISPR corrected organoids. Moreover, increased levels of cGMP were detected. The translational readthrough inducing drug (TRID) PTC124 was investigated as a potential therapeutic. LCA4 retinal organoids exhibited rescue of AIPL1 and PDE6; however, the level of full-length, functional AIPL1 induced through PTC124 treatment was insufficient to reduce cGMP levels and fully rescue the LCA4 phenotype. LCA4 retinal organoids are a valuable platform for the in vitro investigation of the molecular mechanisms that drive photoreceptor loss and for the evaluation of novel therapeutics.

Trophoblast glycoprotein is a new candidate gene for Parkinson’s disease

Parkinson’s disease (PD) is a movement disorder caused by progressive degeneration of the midbrain dopaminergic (mDA) neurons in the substantia nigra pars compacta (SNc). Despite intense research efforts over the past decades, the etiology of PD remains largely unknown. Here, we discovered the involvement of trophoblast glycoprotein (Tpbg) in the development of PD-like phenotypes in mice. Tpbg expression was detected in the ventral midbrain during embryonic development and in mDA neurons in adulthood. Genetic ablation of Tpbg resulted in mild degeneration of mDA neurons in aged mice (12–14 months) with behavioral deficits reminiscent of PD symptoms. Through in silico analysis, we predicted potential TPBG-interacting partners whose functions were relevant to PD pathogenesis; this result was substantiated by transcriptomic analysis of the SNc of aged Tpbg knockout mice. These findings suggest that Tpbg is a new candidate gene associated with PD and provide a new insight into PD pathogenesis.

Genetically modified large animal models for investigating neurodegenerative diseases

Neurodegenerative diseases represent a large group of neurological disorders including Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, and Huntington’s disease. Although this group of diseases show heterogeneous clinical and pathological phenotypes, they share important pathological features characterized by the age-dependent and progressive degeneration of nerve cells that is caused by the accumulation of misfolded proteins. The association of genetic mutations with neurodegeneration diseases has enabled the establishment of various types of animal models that mimic genetic defects and have provided important insights into the pathogenesis. However, most of genetically modified rodent models lack the overt and selective neurodegeneration seen in the patient brains, making it difficult to use the small animal models to validate the effective treatment on neurodegeneration. Recent studies of pig and monkey models suggest that large animals can more faithfully recapitulate pathological features of neurodegenerative diseases. In this review, we discuss the important differences in animal models for modeling pathological features of neurodegenerative diseases, aiming to assist the use of animal models to better understand the pathogenesis and to develop effective therapeutic strategies.

Basal lamina changes in neurodegenerative disorders

Background Neurodegenerative disorders are a group of age-associated diseases characterized by progressive degeneration of the structure and function of the CNS. Two key pathological features of these disorders are blood-brain barrier (BBB) breakdown and protein aggregation. Main body The BBB is composed of various cell types and a non-cellular component---the basal lamina (BL). Although how different cells affect the BBB is well studied, the roles of the BL in BBB maintenance and function remain largely unknown. In addition, located in the perivascular space, the BL is also speculated to regulate protein clearance via the meningeal lymphatic/glymphatic system. Recent studies from our laboratory and others have shown that the BL actively regulates BBB integrity and meningeal lymphatic/glymphatic function in both physiological and pathological conditions, suggesting that it may play an important role in the pathogenesis and/or progression of neurodegenerative disorders. In this review, we focus on changes of the BL and its major components during aging and in neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). First, we introduce the vascular and lymphatic systems in the CNS. Next, we discuss the BL and its major components under homeostatic conditions, and summarize their changes during aging and in AD, PD, and ALS in both rodents and humans. The functional significance of these alterations and potential therapeutic targets are also reviewed. Finally, key challenges in the field and future directions are discussed. Conclusions Understanding BL changes and the functional significance of these changes in neurodegenerative disorders will fill the gap of knowledge in the field. Our goal is to provide a clear and concise review of the complex relationship between the BL and neurodegenerative disorders to stimulate new hypotheses and further research in this field.