Disposition of Proteins and Lipids in Synaptic Membrane Compartments Is Altered in Q175/Q7 Huntington’s Disease Mouse Striatum

Iuliano, Maria; Seeley, Connor; Sapp, Ellen; Jones, Erin L; Martin, Callie; Li, Xueyi; DiFiglia, Marian; Kegel-Gleason, Kimberly B.

doi:10.3389/fnsyn.2021.618391

Cited by 14 publications

(20 citation statements)

References 124 publications

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“…Huntington’s disease (HD) is an inherited progressive brain disease characterized by abnormal motor functions (chorea and dystonia), psychiatric complications (anxiety and depression), and cognitive functions (dementia) ( 99 ). The mutation in the Huntingtin ( HTT ) gene is a well-known cause of HD ( 67 ).…”

Section: Lipidomics In Brain Diseasesmentioning

confidence: 99%

Brain lipidomics: From functional landscape to clinical significance

Yoon

Seo

et al. 2022

Sci. Adv.

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Lipids are crucial components of cellular function owing to their role in membrane formation, intercellular signaling, energy storage, and homeostasis maintenance. In the brain, lipid dysregulations have been associated with the etiology and progression of neurodegeneration and other neurological pathologies. Hence, brain lipids are emerging as important potential targets for the early diagnosis and prognosis of neurological diseases. This review aims to highlight the significance and usefulness of lipidomics in diagnosing and treating brain diseases. We explored lipid alterations associated with brain diseases, paying attention to organ-specific characteristics and the functions of brain lipids. As the recent advances in brain lipidomics would have been impossible without advances in analytical techniques, we provide up-to-date information on mass spectrometric approaches and integrative analysis with other omic approaches. Last, we present the potential applications of lipidomics combined with artificial intelligence techniques and interdisciplinary collaborative research for treating brain diseases with clinical heterogeneities.

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Section: Lipidomics In Brain Diseasesmentioning

confidence: 99%

Brain lipidomics: From functional landscape to clinical significance

Yoon

Seo

et al. 2022

Sci. Adv.

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“…Supporting this observation, mHTT has a strong affinity for lipid membranes and bioengineered lipid bilayers have been shown to function as mHTTEx1 aggregate-promoting structures [57][58][59][60][61] . Aggregation of mHTT in the membrane is likely to cause a disruption of the lipid bilayer, with potentially a distorted localization of membrane receptors, including those required for normal transsynaptic signaling 62 .…”

Section: Discussionmentioning

confidence: 99%

Transmission-selective muscle pathology induced by active propagation of mutant huntingtin across the human neuromuscular synapse

Dinamarca¹,

Colombo

Brykczynska

et al. 2021

Preprint

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A potential explanation for the spatiotemporal accumulation of pathological lesions in the brain of patients with neurodegenerative protein misfolding diseases (PMDs) is cell-to-cell transmission of aggregation-prone, misfolded proteins. Little is known about central to peripheral transmission and its contribution to pathology. We show that transmission of Huntington’s disease- (HD-) associated mutant HTT exon 1 (mHTTEx1) occurs across the neuromuscular junctions in human iPSC cultures and in vivo in wild-type mice. We found that transmission is an active and dynamic process, that happens prior to aggregate formation and is regulated by synaptic activity. Furthermore, we find that transmitted mHTTEx1 causes HD-relevant pathology at a molecular and functional level in human muscle cells, even in the presence of ubiquitous expression mHTTEx1. With this work we uncover a casual-link between mHTTEx1 synaptic transmission and pathology, highlighting the therapeutic potential in blocking toxic protein transmission in PMDs.

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“…Supporting this observation, mHTT has a strong affinity for lipid membranes and bioengineered lipid bilayers have been shown to function as mHTTEx1 aggregate-promoting structures [53][54][55][56][57] . Aggregation of mHTT in the membrane is likely to cause a disruption of the lipid bilayer, with potentially a distorted localization of membrane receptors, including those required for normal transsynaptic signaling 58 .…”

Section: Discussionmentioning

confidence: 99%

Transmission-selective muscle pathology induced by active propagation of mutant huntingtin across the human neuromuscular synapse

Ceballos

Colombo

Brykczynska

et al. 2021

Preprint

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Skeletal muscle dysfunction, wasting and synaptic pathology is a hallmark of Huntingtons disease (HD). Similar as for the nervous system the pathological lesions and clinical symptoms progressively worsen with disease coarse. Cell-to-cell transmission of toxic mutant huntingtin (mHTT) has been shown to occur and could be a potential explanation for the progressive accumulation of pathological lesions and clinical symptoms in time. However, the mechanism and contribution of mHTT cell-to-cell transmission to pathology in an environment of ubiquitous expression of the mutant protein is not well understood. Here, we show that the HD-associated mHTT exon 1 (mHTTEx1) is transmitted from human induced pluripotent stem cell- (hiPSC-) derived motor neurons (MNs) to isogenic hiPSC-derived myotubes across functionally active neuromuscular junctions (NMJ) and in vivo in wild-type mice from the M1 motor cortex to spinal MNs and skeletal muscles. Increased synaptic connectivity and activity enhances transmission. Also, our data reveals that transmission happens prior to aggregate formation and that aggregation occurs progressively with continuous transmission across weeks at the myotube surface. Furthermore, we provide evidence that mHTTEx1 derived from MNs causes defragmentation of mitochondria and exacerbates nuclear aggregation, the latter in the presence of myotube autonomous mHTTEx1. Finally, we find that mHTTEx1 transmission results in decreased myotube contractions, in contrast myotube autonomous expression causes a hyperexcitable-like phenotype. Altogether, our data suggests that mHTTEx1 neuromuscular transmission contributes to skeletal muscle dysfunction in HD, via continuous transmission of the toxic protein already at early preclinical stages of HD and thereby contributes to an increasing accumulation of toxic protein in skeletal muscle, eventually leading to a highly-selective phenotype resulting in a decline of skeletal muscle function. Since multiple studies support a role of synaptic transmission of diverse misfolded proteins, including tau in Alzheimers, alpha-synuclein in Parkinsons, mHTT in HD, tdp-43 in Amyotrophic lateral sclerosis and frontotemporal lobar dementia, in the central nervous system, this process likely represents a common synaptic-linked pathobiological pathway for most neurodegenerative protein misfolding diseases.

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Disposition of Proteins and Lipids in Synaptic Membrane Compartments Is Altered in Q175/Q7 Huntington’s Disease Mouse Striatum

Cited by 14 publications

References 124 publications

Brain lipidomics: From functional landscape to clinical significance

Brain lipidomics: From functional landscape to clinical significance

Transmission-selective muscle pathology induced by active propagation of mutant huntingtin across the human neuromuscular synapse

Transmission-selective muscle pathology induced by active propagation of mutant huntingtin across the human neuromuscular synapse

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