A new chemoenzymatic semisynthetic approach provides novel insight into the role of phosphorylation beyond exon1 of Huntingtin and reveals N-terminal fragment length-dependent distinct mechanisms of aggregation

AbstractHuntington’s disease is a neurodegenerative disorder caused by the expansion of a polyglutamine (poly Q) repeat (>36Q) in the N-terminal domain of the huntingtin protein (Htt), which renders the protein or fragments thereof more prone to aggregate and form inclusions. Although several Htt N-terminal fragments of different lengths have been identified within Htt inclusions, most studies on the mechanisms, sequence, and structural determinants of Htt aggregation have focused on the Htt exon1 (Httex1). Herein, we investigated the aggregation properties of mutant N-terminal Htt fragments of various lengths (Htt171, Htt140, and Htt104) in comparison to mutant Httex1. We also present a new chemoenzymatic semisynthetic strategy that enables site-specific phosphorylation of Htt beyond Httex1. These advances yielded novel insights into how PTMs and structured domains beyond Httex1 influence aggregation mechanisms, kinetics, and fibril morphology of longer N-terminal Htt fragments. We demonstrate that phosphorylation at T107 significantly slowed its aggregation, whereases phosphorylation at T107 and S116 accelerated the aggregation of Htt171, underscoring the importance of crosstalk between different PTMs. We demonstrate that mutant Htt171 proteins aggregate via a different mechanism and form oligomers and fibrillar aggregates with morphological properties that are distinct from that of mutant Httex1. These observations suggest that different N-terminal fragments could have distinct mechanisms of aggregation and that a single polyQ-targeting anti-aggregation strategy may not effectively inhibit the aggregation of all N-terminal Htt fragments. Finally, our results underscore the importance of further studies to investigate the aggregation mechanisms of Htt fragments and how the various fragments interact with each other and influence Htt toxicity, pathology formation, and disease progression.Table of content

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A New Chemoenzymatic Semisynthetic Approach Provides Insight into the Role of Phosphorylation beyond Exon1 of Huntingtin and Reveals N-Terminal Fragment Length-Dependent Distinct Mechanisms of Aggregation

Journal of the American Chemical Society ◽

10.1021/jacs.1c03108 ◽

2021 ◽

Author(s):

Rajasekhar Kolla ◽

Pushparathinam Gopinath ◽

Jonathan Ricci ◽

Andreas Reif ◽

Iman Rostami ◽

...

Keyword(s):

Fragment Length ◽

Terminal Fragment ◽

Insight Into

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Arylsulfatase A (ASA) in Parkinson’s Disease: From Pathogenesis to Biomarker Potential

Brain Sciences ◽

10.3390/brainsci10100713 ◽

2020 ◽

Vol 10 (10) ◽

pp. 713

Author(s):

Efthalia Angelopoulou ◽

Yam Nath Paudel ◽

Chiara Villa ◽

Christina Piperi

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Progression ◽

Neurodegenerative Disorder ◽

In Vivo Studies ◽

Arylsulfatase A ◽

Lysosomal Storage ◽

Potential Implication

Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease, is a clinically heterogeneous disorder, with obscure etiology and no disease-modifying therapy to date. Currently, there is no available biomarker for PD endophenotypes or disease progression. Accumulating evidence suggests that mutations in genes related to lysosomal function or lysosomal storage disorders may affect the risk of PD development, such as GBA1 gene mutations. In this context, recent studies have revealed the emerging role of arylsulfatase A (ASA), a lysosomal hydrolase encoded by the ARSA gene causing metachromatic leukodystrophy (MLD) in PD pathogenesis. In particular, altered ASA levels have been detected during disease progression, and reduced enzymatic activity of ASA has been associated with an atypical PD clinical phenotype, including early cognitive impairment and essential-like tremor. Clinical evidence further reveals that specific ARSA gene variants may act as genetic modifiers in PD. Recent in vitro and in vivo studies indicate that ASA may function as a molecular chaperone interacting with α-synuclein (SNCA) in the cytoplasm, preventing its aggregation, secretion and cell-to-cell propagation. In this review, we summarize the results of recent preclinical and clinical studies on the role of ASA in PD, aiming to shed more light on the potential implication of ASA in PD pathogenesis and highlight its biomarker potential.

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Disease progression mechanism in myelodysplastic syndromes: Insight into the role of the microenvironment

Leukemia Research ◽

10.1016/j.leukres.2011.06.022 ◽

2011 ◽

Vol 35 (11) ◽

pp. 1449-1452 ◽

Cited By ~ 11

Author(s):

Mariko Ishibashi ◽

Hideto Tamura ◽

Kiyoyuki Ogata

Keyword(s):

Disease Progression ◽

Myelodysplastic Syndromes ◽

Insight Into

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Long Non-coding RNA: Insight Into Mechanisms of Alzheimer's Disease

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.821002 ◽

2022 ◽

Vol 14 ◽

Author(s):

Zhen Lan ◽

Yanting Chen ◽

Jiali Jin ◽

Yun Xu ◽

Xiaolei Zhu

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Vital Role ◽

Biological Functions ◽

Non Coding Rna ◽

Non Coding Rnas ◽

Long Non Coding Rna ◽

Insight Into

Alzheimer's disease (AD), a heterogeneous neurodegenerative disorder, is the most common cause of dementia accounting for an estimated 60–80% of cases. The pathogenesis of AD remains unclear, and no curative treatment is available so far. Increasing evidence has revealed a vital role of non-coding RNAs (ncRNAs), especially long non-coding RNAs (lncRNAs), in AD. LncRNAs contribute to the pathogenesis of AD via modulating amyloid production, Tau hyperphosphorylation, mitochondrial dysfunction, oxidative stress, synaptic impairment and neuroinflammation. This review describes the biological functions and mechanisms of lncRNAs in AD, indicating that lncRNAs may provide potential therapeutic targets for the diagnosis and treatment of AD.

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Comparison of bipA Alleles within and across Bordetella Species

Infection and Immunity ◽

10.1128/iai.71.6.3043-3052.2003 ◽

2003 ◽

Vol 71 (6) ◽

pp. 3043-3052 ◽

Cited By ~ 20

Author(s):

Bryna Fuchslocher ◽

Laura L. Millar ◽

Peggy A. Cotter

Keyword(s):

Amino Acid ◽

Intermediate Phase ◽

Expression Patterns ◽

Fine Tuning ◽

Terminal Domain ◽

Amino Acid Repeats ◽

Bacterial Adhesins ◽

Infectious Cycle ◽

Insight Into

ABSTRACT The Bordetella BvgAS signal transduction system controls the expression of at least three phenotypic phases, the Bvg+ or virulent phase, the Bvg− or avirulent phase, and the Bvgi or Bvg intermediate phase, which has been hypothesized to be important for transmission. bipA, the first identified Bvgi-phase gene, encodes a protein with similarity to the well-characterized bacterial adhesins intimin and invasin. Proteins encoded by the bipA genes present in Bordetella pertussis Tohama I and Bordetella bronchiseptica RB50 differ in the number of 90-amino-acid repeats which they possess and in the sequence of the C-terminal domain. To investigate the possibility that bipA alleles segregate according to host specificity and to gain insight into the role of BipA and the Bvgi phase in the Bordetella infectious cycle, we compared bipA alleles across members of the B. bronchiseptica cluster, which includes both human-infective (B. pertussis and B. parapertussis hu) and non-human-infective (B. bronchiseptica and B. parapertussis ov) strains. bipA genes were present in most, but not all, strains. All bipA genes present in B. bronchiseptica strains were identical to bipA of RB50 (at least with regard to the DNA sequence of the 3′ C-terminal-domain-encoding region, the number of 90-amino-acid repeats encoded, and expression patterns). Although all bipA genes present in the other Bordetella strains were identical in the 3′ C-terminal-domain-encoding region to bipA of B. pertussis Tohama I, they varied in the number of 90-amino-acid repeats that they encoded and in expression level. Notably, the genes present in B. parapertussis hu strains were pseudogenes, and the genes present in B. parapertussis ov strains were expressed at significantly reduced levels compared with the levels in B. pertussis and B. bronchiseptica strains. Our results indicate that there is a correlation between specific bipA alleles and specific hosts. They also support the hypothesis that both horizontal gene transfer and fine-tuning of gene expression patterns contribute to the evolution of host adaptation in lineages of the B. bronchiseptica cluster.

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Diagnostic and Prognostic Role of Blood and Cerebrospinal Fluid and Blood Neurofilaments in Amyotrophic Lateral Sclerosis: A Review of the Literature

International Journal of Molecular Sciences ◽

10.3390/ijms20174152 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4152 ◽

Cited By ~ 11

Author(s):

Delia Gagliardi ◽

Megi Meneri ◽

Domenica Saccomanno ◽

Nereo Bresolin ◽

Giacomo Pietro Comi ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Cerebrospinal Fluid ◽

Disease Progression ◽

Neurodegenerative Disorder ◽

Diagnostic Delay ◽

Cytoskeletal Proteins ◽

Pharmacological Intervention ◽

Prognostic Role ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting upper and lower motor neurons (MNs) that still lacks an efficacious therapy. The failure of recent therapeutic trials in ALS, other than depending on the poor knowledge of pathogenic mechanisms responsible for MNs loss, is largely due to diagnostic delay and the lack of reliable biomarkers for diagnosis, prognosis and response to pharmacologic intervention. Neurofilaments (Nfs) are neuron-specific cytoskeletal proteins, whose levels increased in biological fluids proportionally to the degree of axonal damage, both in normal and in pathologic conditions, representing potential biomarkers in various neurological disorders, such as motor neuron disorder (MND). Growing evidence has shown that phosphorylated neurofilaments heavy chain (p-NfH) and neurofilaments light chain (NfL) are increased in blood and cerebrospinal fluid (CSF) of ALS patients compared to healthy and neurological controls and are found to correlate with disease progression. In this review, we reported the most relevant studies investigating the diagnostic and prognostic role of Nfs in ALS. Given their reliability and reproducibility, we consider Nfs as promising and useful biomarkers in diagnosis of MND, early patient identification for inclusion in clinical trials, prediction of disease progression, and response to pharmacological intervention, and we suggest the validation of their measurement in clinical activity.

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Biomarkers and the Role of α-Synuclein in Parkinson’s Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.645996 ◽

2021 ◽

Vol 13 ◽

Author(s):

Tingting Du ◽

Le Wang ◽

Weijin Liu ◽

Guanyu Zhu ◽

Yingchuan Chen ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Progression ◽

Neurodegenerative Disorder ◽

Early Stage ◽

Lewy Bodies ◽

Review Article ◽

Tissue Imaging ◽

Peripheral Tissues

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the presence of α-synuclein (α-Syn)-rich Lewy bodies (LBs) and the preferential loss of dopaminergic (DA) neurons in the substantia nigra (SN) pars compacta (SNpc). However, the widespread involvement of other central nervous systems (CNS) structures and peripheral tissues is now widely documented. The onset of the molecular and cellular neuropathology of PD likely occurs decades before the onset of the motor symptoms characteristic of PD, so early diagnosis of PD and adequate tracking of disease progression could significantly improve outcomes for patients. Because the clinical diagnosis of PD is challenging, misdiagnosis is common, which highlights the need for disease-specific and early-stage biomarkers. This review article aims to summarize useful biomarkers for the diagnosis of PD, as well as the biomarkers used to monitor disease progression. This review article describes the role of α-Syn in PD and how it could potentially be used as a biomarker for PD. Also, preclinical and clinical investigations encompassing genetics, immunology, fluid and tissue, imaging, as well as neurophysiology biomarkers are discussed. Knowledge of the novel biomarkers for preclinical detection and clinical evaluation will contribute to a deeper understanding of the disease mechanism, which should more effectively guide clinical applications.

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