Is the neuropathological ‘gold standard’ diagnosis dead? Implications of clinicopathological findings in an autosomal dominant neurodegenerative disorder

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, whereas frontotemporal lobar degeneration (FTLD) is the most frequent neurodegenerative disorder with a pre-senile onset. The two major neuropathological hallmarks of AD are extracellular amyloid beta plaques and intracellular neurofibrillary tangles. In FTLD the deposition of tau has been observed in a number of cases, but in several brains there is no deposition of tau but instead a positivity for ubiquitin. In some families these diseases are inherited in an autosomal dominant fashion. Genes responsible for familial AD include the amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2), whereas the main genes responsible for familial FTLD are microtubule-associated protein tau gene (MAPT) and progranulin (GRN). Concerning sporadic AD, it is known that the presence of the ε4 allele of the apolipoprotein E gene is a susceptibility factor. A number of additional genetic factors contribute to susceptibility for AD and FTLD.

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Role of Genes and Treatments for Parkinson’s Disease

The Open Biology Journal ◽

10.2174/1874196702008010047 ◽

2020 ◽

Vol 8 (1) ◽

pp. 47-65

Author(s):

Falaq Naz ◽

Yasir Hasan Siddique

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Dopaminergic Neurons ◽

Autosomal Dominant ◽

Neurodegenerative Disorder ◽

Treatment Strategies ◽

Number Of Genes ◽

Permanent Cure

Parkinson’s Disease (PD) is a complex neurodegenerative disorder that mainly results due to the loss of dopaminergic neurons in the substantia nigra of the midbrain. It is well known that dopamine is synthesized in substantia nigra and is transported to the striatum via nigrostriatal tract. Besides the sporadic forms of PD, there are also familial cases of PD and number of genes (both autosomal dominant as well as recessive) are responsible for PD. There is no permanent cure for PD and to date, L-dopa therapy is considered to be the best option besides having dopamine agonists. In the present review, we have described the genes responsible for PD, the role of dopamine, and treatment strategies adopted for controlling the progression of PD in humans.

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Implications of the Orb2 Amyloid Structure in Huntington’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21186910 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6910

Author(s):

Rubén Hervás ◽

Alexey G. Murzin ◽

Kausik Si

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Autosomal Dominant ◽

Neurodegenerative Disorder ◽

Structural Data ◽

Cag Repeat ◽

Functional Amyloid ◽

Drosophila Brain ◽

Structural Insight ◽

The Brain

Huntington’s disease is a progressive, autosomal dominant, neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. As a result, the translated protein, huntingtin, contains an abnormally long polyglutamine stretch that makes it prone to misfold and aggregating. Aggregation of huntingtin is believed to be the cause of Huntington’s disease. However, understanding on how, and why, huntingtin aggregates are deleterious has been hampered by lack of enough relevant structural data. In this review, we discuss our recent findings on a glutamine-based functional amyloid isolated from Drosophila brain and how this information provides plausible structural insight on the structure of huntingtin deposits in the brain.

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Cell signaling pathways in autosomal-dominant leukodystrophy (ADLD): the intriguing role of the astrocytes

Cellular and Molecular Life Sciences ◽

10.1007/s00018-020-03661-1 ◽

2020 ◽

Author(s):

Stefano Ratti ◽

Isabella Rusciano ◽

Sara Mongiorgi ◽

Eric Owusu Obeng ◽

Alessandra Cappellini ◽

...

Keyword(s):

Signaling Pathways ◽

Molecular Mechanisms ◽

Autosomal Dominant ◽

Neurodegenerative Disorder ◽

Nuclear Lamina ◽

Cellular Models ◽

Lamin B1 ◽

Nuclear Alterations ◽

First Time

Abstract Autosomal-dominant leukodystrophy (ADLD) is a rare fatal neurodegenerative disorder with overexpression of the nuclear lamina component, Lamin B1 due to LMNB1 gene duplication or deletions upstream of the gene. The molecular mechanisms responsible for driving the onset and development of this pathology are not clear yet. Vacuolar demyelination seems to be one of the most significant histopathological observations of ADLD. Considering the role of oligodendrocytes, astrocytes, and leukemia inhibitory factor (LIF)-activated signaling pathways in the myelination processes, this work aims to analyze the specific alterations in different cell populations from patients with LMNB1 duplications and engineered cellular models overexpressing Lamin B1 protein. Our results point out, for the first time, that astrocytes may be pivotal in the evolution of the disease. Indeed, cells from ADLD patients and astrocytes overexpressing LMNB1 show severe ultrastructural nuclear alterations, not present in oligodendrocytes overexpressing LMNB1. Moreover, the accumulation of Lamin B1 in astrocytes induces a reduction in LIF and in LIF-Receptor (LIF-R) levels with a consequential decrease in LIF secretion. Therefore, in both our cellular models, Jak/Stat3 and PI3K/Akt axes, downstream of LIF/LIF-R, are downregulated. Significantly, the administration of exogenous LIF can partially reverse the toxic effects induced by Lamin B1 accumulation with differences between astrocytes and oligodendrocytes, highlighting that LMNB1 overexpression drastically affects astrocytic function reducing their fundamental support to oligodendrocytes in the myelination process. In addition, inflammation has also been investigated, showing an increased activation in ADLD patients’ cells.

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The Influence of Huntingtin Protein Size on Nuclear Localization and Cellular Toxicity

The Journal of Cell Biology ◽

10.1083/jcb.141.5.1097 ◽

1998 ◽

Vol 141 (5) ◽

pp. 1097-1105 ◽

Cited By ~ 203

Author(s):

Abigail S. Hackam ◽

Roshni Singaraja ◽

Cheryl L. Wellington ◽

Martina Metzler ◽

Krista McCutcheon ◽

...

Keyword(s):

Nuclear Localization ◽

Huntington Disease ◽

Autosomal Dominant ◽

Neurodegenerative Disorder ◽

Mutant Huntingtin ◽

Cellular Toxicity ◽

Protein Size ◽

Protein Length ◽

Polyglutamine Tract ◽

Increased Susceptibility

Huntington disease is an autosomal dominant neurodegenerative disorder caused by the pathological expansion of a polyglutamine tract. In this study we directly assess the influence of protein size on the formation and subcellular localization of huntingtin aggregates. We have created numerous deletion constructs expressing successively smaller fragments of huntingtin and show that these smaller proteins containing 128 glutamines form both intranuclear and perinuclear aggregates. In contrast, larger NH2-terminal fragments of huntingtin proteins with 128 glutamines form exclusively perinuclear aggregates. These aggregates can form in the absence of endogenous huntingtin. Furthermore, expression of mutant huntingtin results in increased susceptibility to apoptotic stress that is greater with decreasing protein length and increasing polyglutamine size. As both intranuclear and perinuclear aggregates are clearly associated with increased cellular toxicity, this supports an important role for toxic polyglutamine-containing fragments forming aggregates and playing a key role in the pathogenesis of Huntington disease.

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Mitochondrial UQCRC1 mutations cause autosomal dominant parkinsonism with polyneuropathy

Brain ◽

10.1093/brain/awaa279 ◽

2020 ◽

Vol 143 (11) ◽

pp. 3352-3373 ◽

Cited By ~ 2

Author(s):

Chin-Hsien Lin ◽

Pei-I Tsai ◽

Han-Yi Lin ◽

Nobutaka Hattori ◽

Manabu Funayama ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mouse Models ◽

Respiratory Chain ◽

Autosomal Dominant ◽

Neurodegenerative Disorder ◽

Motor Dysfunction ◽

Complex Iii ◽

In Vivo Studies ◽

Familial Parkinson’S Disease

Abstract Parkinson’s disease is a neurodegenerative disorder with a multifactorial aetiology. Nevertheless, the genetic predisposition in many families with multi-incidence disease remains unknown. This study aimed to identify novel genes that cause familial Parkinson’s disease. Whole exome sequencing was performed in three affected members of the index family with a late-onset autosomal-dominant parkinsonism and polyneuropathy. We identified a novel heterozygous substitution c.941A>C (p.Tyr314Ser) in the mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene, which co-segregates with disease within the family. Additional analysis of 699 unrelated Parkinson’s disease probands with autosomal-dominant Parkinson’s disease and 1934 patients with sporadic Parkinson’s disease revealed another two variants in UQCRC1 in the probands with familial Parkinson’s disease, c.931A>C (p.Ile311Leu) and an allele with concomitant splicing mutation (c.70-1G>A) and a frameshift insertion (c.73_74insG, p.Ala25Glyfs*27). All substitutions were absent in 1077 controls and the Taiwan Biobank exome database from healthy participants (n = 1517 exomes). We then assayed the pathogenicity of the identified rare variants using CRISPR/Cas9-based knock-in human dopaminergic SH-SY5Y cell lines, Drosophila and mouse models. Mutant UQCRC1 expression leads to neurite degeneration and mitochondrial respiratory chain dysfunction in SH-SY5Y cells. UQCRC1 p.Tyr314Ser knock-in Drosophila and mouse models exhibit age-dependent locomotor defects, dopaminergic neuronal loss, peripheral neuropathy, impaired respiratory chain complex III activity and aberrant mitochondrial ultrastructures in nigral neurons. Furthermore, intraperitoneal injection of levodopa could significantly improve the motor dysfunction in UQCRC1 p.Tyr314Ser mutant knock-in mice. Taken together, our in vitro and in vivo studies support the functional pathogenicity of rare UQCRC1 variants in familial parkinsonism. Our findings expand an additional link of mitochondrial complex III dysfunction in Parkinson’s disease.

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Predicting Prognosis of Psychosis in Huntington’s Disease: Case Report and Review of Literature

Journal of Neurosciences in Rural Practice ◽

10.4103/jnrp.jnrp_453_16 ◽

2017 ◽

Vol 08 (03) ◽

pp. 469-471

Author(s):

Sujita Kumar Kar ◽

Mohit Kumar Shahi ◽

Adarsh Tripathi ◽

Praveen Kumar Sharma

Keyword(s):

Case Report ◽

Anxiety Disorders ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Autosomal Dominant ◽

Neurodegenerative Disorder ◽

Review Of Literature ◽

Psychiatric Comorbidities ◽

Disease Case ◽

Cognitive Disturbances

ABSTRACTHuntington’s disease (HD) is rare variant of progressive neurodegenerative disorder which follows an autosomal dominant pattern. Psychiatric comorbidities are not uncommon with HD. Mood disorder, cognitive disturbances, anxiety disorders, and psychosis are the psychiatric comorbidities reported with HD. We report here a case of HD, where psychosis developed during illness. Prognosis of psychosis in HD is emphasized in this report with review of literature.

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DCTN1-related Parkinson-plus disorder (Perry syndrome)

Practical Neurology ◽

10.1136/practneurol-2020-002505 ◽

2020 ◽

Vol 20 (4) ◽

pp. 317-319

Author(s):

Daniel Richardson ◽

Meriel M McEntagart ◽

Jeremy D Isaacs

Keyword(s):

Weight Loss ◽

Autosomal Dominant ◽

Neurodegenerative Disorder ◽

Ventilatory Support ◽

Mood Change ◽

Worldwide Distribution ◽

Improve Life Expectancy ◽

Incorrect Diagnosis ◽

Ventilatory Insufficiency ◽

Central Hypoventilation

Dynactin-1 (DCTN1)-related Parkinson-plus disorder (Perry syndrome) is an autosomal dominant neurodegenerative disorder characterised by levodopa-resistant parkinsonism, weight loss, mood change and central hypoventilation. Ventilatory insufficiency is the predominant cause of death. It has been previously described in 87 people from 20 families with a worldwide distribution. It is now recognised as a distinct TDP-43 proteinopathy caused by a pathological mutation in DCTN1. Its rarity and clinical overlap with other neurodegenerative diseases increase the risk of delayed or incorrect diagnosis. Ventilatory support can improve life expectancy but this depends upon its recognition; overall its prognosis remains poor. We report a patient with DCTN1-related Parkinson-plus disorder, in whom genetic confirmation came only after death.

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Huntington Disease: Clinical, Genetic, and Social Aspects

Journal of Geriatric Psychiatry and Neurology ◽

10.1177/089198879801100204 ◽

1998 ◽

Vol 11 (2) ◽

pp. 61-70 ◽

Cited By ~ 26

Author(s):

Martha A. Nance

Keyword(s):

Huntington Disease ◽

Collaborative Research ◽

Autosomal Dominant ◽

Trinucleotide Repeat ◽

Clinical Symptoms ◽

Neurodegenerative Disorder ◽

Social Aspects ◽

Clinical Genetic ◽

Behavioral Disturbances ◽

Neurogenetic Disorders

Huntington disease (HD) is a fascinating neurodegenerative disorder whose features straddle the boundaries of psychiatry, neurology, and genetics. The clinical symptoms of HD consist of a triad of motor, cognitive, and psychiatric/behavioral disturbances. In 1993, the HD Collaborative Research Group identified the gene and the mutation responsible for HD. HD was one of the first neurodegenerative disorders discovered to be caused by a novel mutational mechanism known as trinucleotide repeat expansion. Since then, HD has been the model for autosomal dominant neurogenetic disorders. The clinical, pathological, and genetic aspects of the disease are reviewed and some of the questions that remain to be answered by researchers of the 21st century are outlined.

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Efficacy of GLP-1 Agonist Therapy in Autosomal Dominant WFS1-Related Disorder: A Case Report

Hormone Research in Paediatrics ◽

10.1159/000510852 ◽

2020 ◽

pp. 1-6

Author(s):

Kevin J. Scully ◽

Joseph I. Wolfsdorf

Keyword(s):

Diabetes Mellitus ◽

Autosomal Dominant ◽

Neurodegenerative Disorder ◽

Low Frequency ◽

Sensorineural Deafness ◽

Indirect Evidence ◽

Wolfram Syndrome ◽

Related Disorder ◽

History Of ◽

Congenital Strabismus

Background: Wolfram syndrome is a rare neurodegenerative disorder, characterized by the presence of diabetes insipidus, diabetes mellitus, optic atrophy, and sensorineural deafness. The majority of cases are due to autosomal recessive biallelic variants in the WFS1 gene; however, pathogenic autosomal dominant (AD) mutations have also been described. Glucagon-like peptide (GLP-1) agonists have been studied in both animal models and humans with classic Wolfram syndrome. Case: We present a 15-year-old female with a personal and family history of congenital strabismus, bilateral cataracts, low-frequency sensorineural hearing loss, and diabetes mellitus. Trio whole exome sequencing revealed a previously unknown maternally inherited heterozygous variant in exon 8 of the WFS1 gene c.2605_2616del12 p.Ser869_His872del, leading to the diagnosis of AD WFS1-related disorder. Treatment with a GLP-1 agonist resulted in marked improvement in glycemic control and discontinuation of insulin therapy. This patient’s response to a GLP-1 agonist provides suggestive indirect evidence for a role of WFS1 on β-cell endoplasmic reticulum stress and suggests that treatment with a GLP-1 agonist should be considered in patients with dominant forms of WS.

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