Novel Lactulose and Melibiose Targeting Autophagy to Reduce PolyQ Aggregation in Cell Models of Spinocerebellar Ataxia 3

Lin, Cheng-Wei; Wu, Yih‐Ru; Yang, Jinn-Moon; Chen, Wan-Ling; Chao, Chuck C.‐K.; Chen, I-Cheng; Lin, Te-Hsien; Wu, Yi-Ci; Hsu, Kai‐Cheng; Chen, Chiung‐Mei; Lee, Guan-Chiun; Hsieh-Li, Hsiu-Mei; Lee, Chi-Mei; Lee‐Chen, Guey‐Jen

doi:10.2174/1871527314666150821101522

Cited by 25 publications

(32 citation statements)

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“…LC3 and p62 serve as the useful marker of autophagy induction and clearance of protein aggregates via autophagosome, respectively. Numerous studies using different interventions, such as far‐infrared radiation and chemical enhancers of autophagy, have consistently achieved a decrease of polyQ expression in SCA type 3 (SCA3) by increasing the LC3‐II concentration and decreasing P62 expression. Thus, autophagy induction could potentially be used as a therapeutic strategy for controlling the progression of SCA by ameliorating mutant‐protein‐induced neuron death .…”

Section: Discussionmentioning

confidence: 99%

Treadmill training increases the motor activity and neuron survival of the cerebellum in a mouse model of spinocerebellar ataxia type 1

Chuang

Chang

Soong

et al. 2019

The Kaohsiung J of Med Scie

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Spinocerebellar ataxia (SCA) type 1 (SCA1) is a rare autosomal dominant disorder that is characterized by worsening of disordered coordination, ataxia of the trunk, and other neurological symptoms. Physical activity improves both mobility and the daily living activities of patients with SCA. Intervention with daily regular treadmill exercise may slow the deterioration of cerebellar neurons in SCA1. Therefore, the signal changes and performance of cerebellar neurons after exercise in SCA1 was investigated in this study.We employed a transgenic mouse model of SCA1, generated by amplifying the cytosineadenine-guanine trinucleotide repeat expansions, and the mice underwent 1 month of moderate daily treadmill exercise for 1 hour. The rotarod test revealed that the motor function of the SCA1 mice that underwent training was superior to that of the control SCA1 mice, which did not undergo training. Moreover, the cerebellar pathology revealed preserved Purkinje neurons stained by carbindin with an increase of the neuronal Per Arnt Sim domain protein 4, a key regulation in the structural and functional plasticity of neurons, in the excised SCA1 mice relative to the controls. The mechanism was related to an increase of phosphorylation of ribosomal protein S6, a downstream target of the mammalian target of rapamycin pathway, but not to autophagy activation. This study determined that regular treadmill exercise may play a crucial role in the viable support of cerebellar neurons in SCA1. K E Y W O R D S neuronal Per Arnt Sim domain protein 4, Purkinje neurons, ribosomal protein S6, Spinocerebellar ataxia type 1, treadmill training

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Section: Discussionmentioning

confidence: 99%

Treadmill training increases the motor activity and neuron survival of the cerebellum in a mouse model of spinocerebellar ataxia type 1

Chuang

Chang

Soong

et al. 2019

The Kaohsiung J of Med Scie

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“…Trehalose, a compound already described in the above section as a chemical chaperone able to influence protein folding, is also an mTOR‐independent autophagy inducer that can enhance clearance of aggregation‐prone mutant HTT and ATXN3 and protect against apoptotic insults in cells via its autophagy‐inducing properties . The combinatory effects of its autophagy‐inducing and chemical chaperone activities, together with its lack of toxicity, places trehalose as a potentially interesting compound for polyQ disease therapy.…”

Section: Therapeutic Strategies For Polyq Diseasesmentioning

confidence: 95%

Discovery of Therapeutic Approaches for Polyglutamine Diseases: A Summary of Recent Efforts

Duarte‐Silva

Maciel

2016

Medicinal Research Reviews

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Polyglutamine (PolyQ) diseases are a group of neurodegenerative disorders caused by the expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the coding region of specific genes. This leads to the production of pathogenic proteins containing critically expanded tracts of glutamines. Although polyQ diseases are individually rare, the fact that these nine diseases are irreversibly progressive over 10 to 30 years, severely impairing and ultimately fatal, usually implicating the full-time patient support by a caregiver for long time periods, makes their economic and social impact quite significant. This has led several researchers worldwide to investigate the pathogenic mechanism(s) and therapeutic strategies for polyQ diseases. Although research in the field has grown notably in the last decades, we are still far from having an effective treatment to offer patients, and the decision of which compounds should be translated to the clinics may be very challenging. In this review, we provide a comprehensive and critical overview of the most recent drug discovery efforts in the field of polyQ diseases, including the most relevant findings emerging from two different types of approaches-hypothesis-based candidate molecule testing and hypothesis-free unbiased drug screenings. We hereby summarize and reflect on the preclinical studies as well as all the clinical trials performed to date, aiming to provide a useful framework for increasingly successful future drug discovery and development efforts.

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“…However, in these pathologies, autophagy fails to remove toxic molecules due to their abundance and to the inhibitory effects of long polyQ mutation on mechanism initiating autophagy [167]. Consistently, pharmacological treatments targeting autophagy provided beneficial effects in several models of hereditary cerebellar ataxia [168][169][170][171]. Moreover, positive outcomes associated with changes in autophagy were also induced by motor training administered at presymptomatic stages in the tambaleante (tbl) mouse model of ataxia [172].…”

Section: Cellular Mechanisms Underlying Functional Cerebellar Reservementioning

confidence: 94%

Consensus Paper. Cerebellar Reserve: From Cerebellar Physiology to Cerebellar Disorders

et al. 2019

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Cerebellar reserve refers to the capacity of the cerebellum to compensate for tissue damage or loss of function resulting from many different etiologies. When the inciting event produces acute focal damage (e.g., stroke, trauma), impaired cerebellar function may be compensated for by other cerebellar areas or by extracerebellar structures (i.e., structural cerebellar reserve). In contrast, when pathological changes compromise cerebellar neuronal integrity gradually leading to cell death (e.g., metabolic and immune-mediated cerebellar ataxias, neurodegenerative ataxias), it is possible that the affected area itself can compensate for the slowly evolving cerebellar lesion (i.e., functional cerebellar reserve). Here, we examine cerebellar reserve from the perspective of the three cornerstones of clinical ataxiology: control of ocular movements, coordination of voluntary axial and appendicular movements, and cognitive functions. Current evidence indicates that cerebellar reserve is potentiated by environmental enrichment through the mechanisms of autophagy and synaptogenesis, suggesting that cerebellar reserve is not rigid or fixed, but exhibits plasticity potentiated by experience. These conclusions have therapeutic implications. During the period when cerebellar reserve is preserved, treatments should be directed at stopping disease progression and/or limiting the pathological process. Simultaneously, cerebellar reserve may be potentiated using multiple approaches. Potentiation of cerebellar reserve may lead to compensation and restoration of function in the setting of cerebellar diseases, and also in disorders primarily of the cerebral hemispheres by enhancing cerebellar mechanisms of action. It therefore appears that cerebellar reserve, and the underlying plasticity of cerebellar microcircuitry that enables it, may be of critical neurobiological importance to a wide range of neurological/neuropsychiatric conditions.

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Novel Lactulose and Melibiose Targeting Autophagy to Reduce PolyQ Aggregation in Cell Models of Spinocerebellar Ataxia 3

Cited by 25 publications

References 0 publications

Treadmill training increases the motor activity and neuron survival of the cerebellum in a mouse model of spinocerebellar ataxia type 1

Treadmill training increases the motor activity and neuron survival of the cerebellum in a mouse model of spinocerebellar ataxia type 1

Discovery of Therapeutic Approaches for Polyglutamine Diseases: A Summary of Recent Efforts

Consensus Paper. Cerebellar Reserve: From Cerebellar Physiology to Cerebellar Disorders

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