Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that was originally discovered in the population from the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region in Quebec. Although the disease progression of ARSACS may start in early childhood, cases with later onset have also been observed. Spasticity and ataxia could be common phenotypes, and retinal optic nerve hypermyelination is detected in the majority of patients. Other symptoms, such as pes cavus, ataxia and limb deformities, are also frequently observed in affected individuals. More than 200 mutations have been discovered in the SACS gene around the world. Besides French Canadians, SACS genetics have been extensively studied in Tunisia or Japan. Recently, emerging studies discovered SACS mutations in several other countries. SACS mutations could be associated with pathogenicity either in the homozygous or compound heterozygous stages. Sacsin has been confirmed to be involved in chaperon activities, controlling the microtubule balance or cell migration. Additionally, sacsin may also play a crucial role in regulating the mitochondrial functions. Through these mechanisms, it may share common mechanisms with other neurodegenerative diseases. Further studies are needed to define the exact functions of sacsin. This review introduces the genetic mutations discovered in the SACS gene and discusses its pathomechanisms and its possible involvement in other neurodegenerative diseases.

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Papillon-Lefevre Syndrome: Challenge for Periodontal Management

Journal of Nepalese Society of Periodontology and Oral Implantology ◽

10.3126/jnspoi.v3i2.30891 ◽

2019 ◽

Vol 3 (2) ◽

pp. 84-86

Author(s):

Krishna Prasad Lamichhane ◽

Shaili Pradhan ◽

Ranjita Shreshta Gorkhali ◽

Pramod Kumar Koirala

Keyword(s):

Significant Role ◽

Autosomal Recessive ◽

Clinical Manifestations ◽

Autosomal Recessive Disorder ◽

Genetic Mutations ◽

Rare Autosomal Recessive Disorder ◽

Diagnosis And Management ◽

Periodontal Destruction ◽

Palmoplantar Keratosis

Papillon-Lefèvre syndrome (PLS) is a rare autosomal recessive disorder associated with rapidly progressing periodontitis leading to premature loss of deciduous and permanent dentition and diffuse palmoplantar keratosis. Immunologic alterations, genetic mutations, and role of bacteria are some aetiologic factors. Patients present with early periodontal destruction, so periodontists play a significant role in diagnosis and management. This paper reports a case of Papillon- Lefevre syndrome with its clinical manifestations and challenges for periodontal management which was diagnosed in dental department.

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AIF3 splicing switch triggers neurodegeneration

Molecular Neurodegeneration ◽

10.1186/s13024-021-00442-7 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Shuiqiao Liu ◽

Mi Zhou ◽

Zhi Ruan ◽

Yanan Wang ◽

Calvin Chang ◽

...

Keyword(s):

Cell Death ◽

Neurodegenerative Diseases ◽

Mitochondrial Dysfunction ◽

Nuclear Translocation ◽

Chromatin Condensation ◽

Neuronal Cell ◽

Adult Brain ◽

Postmortem Brain ◽

Mitochondrial Functions

Abstract Background Apoptosis-inducing factor (AIF), as a mitochondrial flavoprotein, plays a fundamental role in mitochondrial bioenergetics that is critical for cell survival and also mediates caspase-independent cell death once it is released from mitochondria and translocated to the nucleus under ischemic stroke or neurodegenerative diseases. Although alternative splicing regulation of AIF has been implicated, it remains unknown which AIF splicing isoform will be induced under pathological conditions and how it impacts mitochondrial functions and neurodegeneration in adult brain. Methods AIF splicing induction in brain was determined by multiple approaches including 5′ RACE, Sanger sequencing, splicing-specific PCR assay and bottom-up proteomic analysis. The role of AIF splicing in mitochondria and neurodegeneration was determined by its biochemical properties, cell death analysis, morphological and functional alterations and animal behavior. Three animal models, including loss-of-function harlequin model, gain-of-function AIF3 knockin model and conditional inducible AIF splicing model established using either Cre-loxp recombination or CRISPR/Cas9 techniques, were applied to explore underlying mechanisms of AIF splicing-induced neurodegeneration. Results We identified a nature splicing AIF isoform lacking exons 2 and 3 named as AIF3. AIF3 was undetectable under physiological conditions but its expression was increased in mouse and human postmortem brain after stroke. AIF3 splicing in mouse brain caused enlarged ventricles and severe neurodegeneration in the forebrain regions. These AIF3 splicing mice died 2–4 months after birth. AIF3 splicing-triggered neurodegeneration involves both mitochondrial dysfunction and AIF3 nuclear translocation. We showed that AIF3 inhibited NADH oxidase activity, ATP production, oxygen consumption, and mitochondrial biogenesis. In addition, expression of AIF3 significantly increased chromatin condensation and nuclear shrinkage leading to neuronal cell death. However, loss-of-AIF alone in harlequin or gain-of-AIF3 alone in AIF3 knockin mice did not cause robust neurodegeneration as that observed in AIF3 splicing mice. Conclusions We identified AIF3 as a disease-inducible isoform and established AIF3 splicing mouse model. The molecular mechanism underlying AIF3 splicing-induced neurodegeneration involves mitochondrial dysfunction and AIF3 nuclear translocation resulting from the synergistic effect of loss-of-AIF and gain-of-AIF3. Our study provides a valuable tool to understand the role of AIF3 splicing in brain and a potential therapeutic target to prevent/delay the progress of neurodegenerative diseases.

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Novel compound heterozygous mutation in SACS gene leads to a milder autosomal recessive spastic ataxia of Charlevoix‐Saguenay, ARSACS , in a Finnish family

Clinical Case Reports ◽

10.1002/ccr3.722 ◽

2016 ◽

Vol 4 (12) ◽

pp. 1151-1156 ◽

Cited By ~ 7

Author(s):

Johanna Palmio ◽

Mikko Kärppä ◽

Peter Baumann ◽

Sini Penttilä ◽

Jukka Moilanen ◽

...

Keyword(s):

Autosomal Recessive ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Spastic Ataxia

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The Muscle-Brain Axis and Neurodegenerative Diseases: The Key Role of Mitochondria in Exercise-Induced Neuroprotection

International Journal of Molecular Sciences ◽

10.3390/ijms22126479 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6479

Author(s):

Johannes Burtscher ◽

Grégoire P. Millet ◽

Nicolas Place ◽

Bengt Kayser ◽

Nadège Zanou

Keyword(s):

Skeletal Muscle ◽

Neurodegenerative Diseases ◽

Protective Factor ◽

Motor Disorder ◽

Regular Exercise ◽

Mitochondrial Transfer ◽

Mitochondrial Functions ◽

Exercise Induced ◽

The Brain

Regular exercise is associated with pronounced health benefits. The molecular processes involved in physiological adaptations to exercise are best understood in skeletal muscle. Enhanced mitochondrial functions in muscle are central to exercise-induced adaptations. However, regular exercise also benefits the brain and is a major protective factor against neurodegenerative diseases, such as the most common age-related form of dementia, Alzheimer’s disease, or the most common neurodegenerative motor disorder, Parkinson’s disease. While there is evidence that exercise induces signalling from skeletal muscle to the brain, the mechanistic understanding of the crosstalk along the muscle–brain axis is incompletely understood. Mitochondria in both organs, however, seem to be central players. Here, we provide an overview on the central role of mitochondria in exercise-induced communication routes from muscle to the brain. These routes include circulating factors, such as myokines, the release of which often depends on mitochondria, and possibly direct mitochondrial transfer. On this basis, we examine the reported effects of different modes of exercise on mitochondrial features and highlight their expected benefits with regard to neurodegeneration prevention or mitigation. In addition, knowledge gaps in our current understanding related to the muscle–brain axis in neurodegenerative diseases are outlined.

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Novel compound heterozygous mutations of the SACS gene in autosomal recessive spastic ataxia of Charlevoix-Saguenay

Clinical Neurology and Neurosurgery ◽

10.1016/j.clineuro.2011.12.019 ◽

2012 ◽

Vol 114 (6) ◽

pp. 746-747 ◽

Cited By ~ 1

Author(s):

Rie Haga ◽

Yasuo Miki ◽

Yukihisa Funamizu ◽

Tomoya Kon ◽

Chieko Suzuki ◽

...

Keyword(s):

Autosomal Recessive ◽

Compound Heterozygous ◽

Spastic Ataxia ◽

Compound Heterozygous Mutations

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Sacsin-related ataxia (ARSACS): Expanding the genotype upstream from the gigantic exon

Neurology ◽

10.1212/01.wnl.0000204300.94261.ea ◽

2006 ◽

Vol 66 (7) ◽

pp. 1103-1104 ◽

Cited By ~ 37

Author(s):

Y. Ouyang ◽

Y. Takiyama ◽

K. Sakoe ◽

H. Shimazaki ◽

T. Ogawa ◽

...

Keyword(s):

Autosomal Recessive ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Spastic Ataxia

The authors describe a Japanese autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) patient with a compound heterozygous mutation (32627-32636delACACTGTTAC and 31760delT) in a new exon of the SACS gene. The new exons upstream of the gigantic one should be analyzed when a case is clinically compatible with ARSACS, even without any mutation in the gigantic exon.

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Mitochondrial Dynamics: A Key Role in Neurodegeneration and a Potential Target for Neurodegenerative Disease

Frontiers in Neuroscience ◽

10.3389/fnins.2021.654785 ◽

2021 ◽

Vol 15 ◽

Author(s):

Danying Yang ◽

Jun Ying ◽

Xifeng Wang ◽

Tiancheng Zhao ◽

Sungtae Yoon ◽

...

Keyword(s):

Cell Death ◽

Neurodegenerative Diseases ◽

Neurodegenerative Disease ◽

Significant Influence ◽

Mitochondrial Dynamics ◽

Therapeutic Strategies ◽

Pathological Process ◽

Mitochondrial Functions ◽

Associated Proteins

In neurodegenerative diseases, neurodegeneration has been related to several mitochondrial dynamics imbalances such as excessive fragmentation of mitochondria, impaired mitophagy, and blocked mitochondria mitochondrial transport in axons. Mitochondria are dynamic organelles, and essential for energy conversion, neuron survival, and cell death. As mitochondrial dynamics have a significant influence on homeostasis, in this review, we mainly discuss the role of mitochondrial dynamics in several neurodegenerative diseases. There is evidence that several mitochondrial dynamics-associated proteins, as well as related pathways, have roles in the pathological process of neurodegenerative diseases with an impact on mitochondrial functions and metabolism. However, specific pathological mechanisms need to be better understood in order to propose new therapeutic strategies targeting mitochondrial dynamics that have shown promise in recent studies.

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Co-existence of phenylketonuria either with maple syrup urine disease or Sandhoff disease in two patients from Iran: emphasizing the role of consanguinity

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2016-0096 ◽

2016 ◽

Vol 29 (10) ◽

Cited By ~ 4

Author(s):

Maryam Abiri ◽

Saeed Talebi ◽

Jouni Uitto ◽

Leila Youssefian ◽

Hassan Vahidnezhad ◽

...

Keyword(s):

Maple Syrup Urine Disease ◽

Autosomal Recessive ◽

Sandhoff Disease ◽

Compound Heterozygous ◽

Inborn Errors ◽

Maple Syrup ◽

Cherry Red Spot ◽

Urine Disease ◽

Autosomal Recessive Manner

AbstractMost inborn errors of metabolism (IEMs) are inherited in an autosomal recessive manner. IEMs are one of the major concerns in Iran due to its extensive consanguineous marriages. Herein, we report two patients with two co-existent IEMs: a girl affected by classic phenylketonuria (PKU) and maple syrup urine disease (MSUD) and a male patient affected with Sandhoff disease and PKU, where Sandhoff disease was suspected due to the presence of a cherry-red spot in the eyes at 6 months which is unrelated to PKU. Sequencing of candidate genes in the first patient revealed one novel and three recurrent compound heterozygous mutations of p.Ser231Pro and p.Ala300Ser in the

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The Michael J. Fox Foundation for Parkinson’s Research Strategy to Advance Therapeutic Development of PINK1 and Parkin

Biomolecules ◽

10.3390/biom9080296 ◽

2019 ◽

Vol 9 (8) ◽

pp. 296 ◽

Cited By ~ 3

Author(s):

Shalini Padmanabhan ◽

Nicole K. Polinski ◽

Liliana B. Menalled ◽

Marco A.S. Baptista ◽

Brian K. Fiske

Keyword(s):

Autosomal Recessive ◽

Research Strategy ◽

Activation Mechanism ◽

High Quality Research ◽

Innate And Adaptive Immunity ◽

Genetics Research ◽

Mitochondrial Functions ◽

Therapeutic Development ◽

Strategic Funding

The role of mitochondria in Parkinson’s disease (PD) has been investigated since the 1980s and is gaining attention with recent advances in PD genetics research. Mutations in PRKN and PTEN-Induced Putative Kinase 1 (PINK1) are well-established causes of autosomal recessive early-onset PD. Genetic and biochemical studies have revealed that PINK1 and Parkin proteins function together in the same biological pathway to govern mitochondrial quality control. These proteins have also been implicated in the regulation of innate and adaptive immunity and other mitochondrial functions. Additionally, structural studies on Parkin have delineated an activation mechanism and have identified druggable regions that are currently being explored by academic and industry groups. To de-risk therapeutic development for these genetic targets, The Michael J. Fox Foundation for Parkinson’s Research (MJFF) has deployed a strategic funding and enabling framework that brings together the research community to discuss important breakthroughs and challenges in research on PINK1-Parkin biology, supports collaborative initiatives to further our understanding within this field and develops high-quality research tools and assays that are widely available to all researchers. The Foundation’s efforts are leading to significant advances in understanding of the underlying biology of these genes, proteins and pathways and in the development of Parkinson’s therapies.

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The Role of Genetic Mutations in Gene LPIN2 in Majeed Syndrome

10.47363/jpr/2020(1)107 ◽

2020 ◽

pp. 1-3

Author(s):

Shahin Asadi ◽

Keyword(s):

Blood Cells ◽

Autosomal Recessive ◽

Slow Growth ◽

Chronic Recurrent Multifocal Osteomyelitis ◽

Genetic Mutations ◽

Shortness Of Breath ◽

Sweet Syndrome ◽

Multifocal Osteomyelitis ◽

Autosomal Recessive Pattern

Majeed syndrome is characterized by recurrent episodes of fever and inflammation in the bones and skin. The two main features of this condition are chronic recurrent multifocal osteomyelitis (CRMO) and congenital dyserythropoietic anemia (CDA). CRMO causes recurrent episodes of pain and joint swelling which can lead to complications such as slow growth and the development of joint deformities called contractures. CDA involves a shortage of red blood cells which can lead to fatigue (tiredness), weakness, pale skin, and shortness of breath. Most people with Majeed syndrome also develop inflammatory disorders of the skin, most often a condition known as Sweet syndrome. Majeed syndrome results from mutations in the LPIN2 gene. This condition is inherited in an autosomal recessive pattern.

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