Editing Huntington's disease (section)

===Cellular changes===

[[File:Neuron with mHTT inclusion zoomed.jpg|thumb|left|alt=Closer view of neuron having a large central core with several tendrils branching out some of which branch again, the core of the contains an orange blob about a quarter of its diameter | A microscope image of a neuron with an [[inclusion body]] (stained orange) caused by HD, image width 250&nbsp;[[micrometre|μm]]]]

The toxic action of mHtt may manifest and produce the HD pathology through multiple cellular changes.<ref name="pmid14585171">{{cite journal | vauthors = Rubinsztein DC, Carmichael J | title = Huntington's disease: molecular basis of neurodegeneration | journal = Expert Reviews in Molecular Medicine | volume = 5 | issue = 20 | pages = 1–21 | date = August 2003 | pmid = 14585171 | doi = 10.1017/S1462399403006549 | s2cid = 28435830 }}</ref><ref name="pmid2136787">{{cite journal | vauthors = Bloch M, Hayden MR | title = Opinion: predictive testing for Huntington disease in childhood: challenges and implications | journal = American Journal of Human Genetics | volume = 46 | issue = 1 | pages = 1–4 | date = January 1990 | pmid = 2136787 | pmc = 1683548 }}</ref> In its mutant (polyglutamine expanded) form, the protein is more prone to cleavage that creates shorter fragments containing the polyglutamine expansion.<ref name="pmid14585171"/>  These protein fragments have a propensity to undergo [[misfolding]] and aggregation, yielding fibrillar aggregates in which non-native polyglutamine β-strands from multiple proteins are bonded together by hydrogen bonds.<ref name="hdprimer">{{cite journal | vauthors = Bates GP, Dorsey R, Gusella JF, Hayden MR, Kay C, Leavitt BR, Nance M, Ross CA, Scahill RI, Wetzel R, Wild EJ, Tabrizi SJ | title = Huntington disease | journal = Nature Reviews. Disease Primers | volume = 1 | pages = 15005 | date = April 2015 | pmid = 27188817 | doi = 10.1038/nrdp.2015.5 | author-link12 = Sarah Tabrizi | s2cid = 25759303 }}</ref> These aggregates share the same fundamental cross-beta [[amyloid]] architecture seen in other [[Proteopathies|protein deposition diseases]].<ref name="fibrilstruc">{{cite journal | vauthors = Matlahov I, van der Wel PC | title = Conformational studies of pathogenic expanded polyglutamine protein deposits from Huntington's disease | journal = Experimental Biology and Medicine | volume = 244 | issue = 17 | pages = 1584–1595 | date = December 2019 | pmid = 31203656 | pmc = 6920524 | doi = 10.1177/1535370219856620 | s2cid = 189944779 }}</ref> Over time, the aggregates accumulate to form [[inclusion bodies]] within cells, ultimately interfering with neuronal function.<ref name="hdprimer"/><ref name="pmid14585171"/> Inclusion bodies have been found in both the [[cell nucleus]] and [[cytoplasm]].<ref name="pmid14585171"/> Inclusion bodies in cells of the brain are one of the earliest pathological changes, and some experiments have found that they can be [[neurotoxicity|toxic]] for the cell, but other experiments have shown that they may form as part of the body's defense mechanism and help protect cells.<ref name="pmid14585171"/>

Several pathways by which mHtt may cause cell death have been identified. These include effects on [[Chaperone (protein)|chaperone proteins]], which help fold proteins and remove misfolded ones; interactions with [[caspase]]s, which play a role in the [[apoptosis|process of removing cells]]; the [[excitotoxicity|toxic effects of glutamine on nerve cells]]; impairment of energy production within cells; and effects on the expression of genes.<ref name="hdprimer"/><ref name="urlNature Clinical Practice Neurology | Mechanisms of Disease: histone modifications in Huntingtons disease | Article">{{cite journal | vauthors = Sadri-Vakili G, Cha JH | title = Mechanisms of disease: Histone modifications in Huntington's disease | journal = Nature Clinical Practice. Neurology | volume = 2 | issue = 6 | pages = 330–338 | date = June 2006 | pmid = 16932577 | doi = 10.1038/ncpneuro0199 | s2cid = 12474262 }}</ref>

Mutant huntingtin protein has been found to play a key role in [[mitochondrial dysfunction]].<ref name="Liu">{{cite journal | vauthors = Liu Z, Zhou T, Ziegler AC, Dimitrion P, Zuo L | title = Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications | journal = Oxidative Medicine and Cellular Longevity | volume = 2017 | pages = 2525967 | date = 2017 | pmid = 28785371 | pmc = 5529664 | doi = 10.1155/2017/2525967 | doi-access = free }}</ref>  The impairment of [[mitochondrial electron transport chains|mitochondrial electron transport]] can result in higher levels of [[oxidative stress]] and release of [[reactive oxygen species]].<ref name="pmid27662334">{{cite journal | vauthors = Kumar A, Ratan RR | title = Oxidative Stress and Huntington's Disease: The Good, The Bad, and The Ugly | journal = Journal of Huntington's Disease | volume = 5 | issue = 3 | pages = 217–237 | date = October 2016 | pmid = 27662334 | pmc = 5310831 | doi = 10.3233/JHD-160205 }}</ref>

Glutamine is known to be [[Excitotoxin|excitotoxic]] when present in large amounts, that can cause damage to numerous cellular structures.  Excessive glutamine is not found in HD, but the interactions of the altered huntingtin protein with numerous proteins in neurons lead to an increased vulnerability to glutamine.  The increased vulnerability is thought to result in excitotoxic effects from normal glutamine levels.<ref name="hdprimer"/>

A somatic expansion of CAG repeats is involved in the progression of the disease. Over decades, the HTT gene first sees its CAG repeats expand to about 80 copies: the 35+ CAG locus causes additional slippage errors that expand the repeat. Then the process accelerates, reaching 150 copies within years. There is no significant toxic effect on the cell until 150 copies, at which point a large number of genes become progressively dysregulated. Over months, the [[medium spiny neuron]] slowly loses its cell identity until cell death pathways are activated.<ref>{{cite journal |last1=Handsaker |first1=Robert E. |last2=Kashin |first2=Seva |last3=Reed |first3=Nora M. |last4=Tan |first4=Steven |last5=Lee |first5=Won-Seok |last6=McDonald |first6=Tara M. |last7=Morris |first7=Kiely |last8=Kamitaki |first8=Nolan |last9=Mullally |first9=Christopher D. |last10=Morakabati |first10=Neda R. |last11=Goldman |first11=Melissa |last12=Lind |first12=Gabriel |last13=Kohli |first13=Rhea |last14=Lawton |first14=Elisabeth |last15=Hogan |first15=Marina |last16=Ichihara |first16=Kiku |last17=Berretta |first17=Sabina |last18=McCarroll |first18=Steven A. |title=Long somatic DNA-repeat expansion drives neurodegeneration in Huntington’s disease |journal=Cell |date=February 2025 |volume=188 |issue=3 |pages=623–639.e19 |doi=10.1016/j.cell.2024.11.038|doi-access=free }}</ref>