Traffic signaling: new functions of huntingtin and axonal transport in neurological disease

  title={Traffic signaling: new functions of huntingtin and axonal transport in neurological disease},
  author={H{\'e}l{\`e}ne Vitet and Vicky Brandt and Fr{\'e}d{\'e}ric Saudou},
  journal={Current Opinion in Neurobiology},
Over the past twenty years there have been numerous advances in our understanding of Huntington's disease (HD) and other neurodegenerative proteopathies such as Alzheimer's disease and Parkinson's disease. In each case, disease-specific proteins are expressed and accumulate; what has been less clear is precisely what problems are caused by the accumulation. Recently we have begun to appreciate that increased protein levels or changes in the ratios of different isoforms affect the movement of… 
10 Citations
Mitochondrial Abnormalities and Synaptic Damage in Huntington's Disease: a Focus on Defective Mitophagy and Mitochondria-Targeted Therapeutics.
Recent research in Huntington's disease progression is discussed, including developments of cell and mouse models, cellular changes, mitochondrial abnormalities, DNA damage, bioenergetics, oxidative stress, mitophagy, and therapeutics strategies in HD.
When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer’s and Huntington’s Disease
  • S. D’Mello
  • Medicine
    International journal of molecular sciences
  • 2021
This review covers what is known about the role of these three groups of kinases in the brain and in the pathogenesis of the two neurodegenerative disorders and the potential of targeting GSK3, p38 MAPK and CDKS as effective therapeutics.
A possible non-proteolytic role of ubiquitin conjugation in alleviating the pathology of Huntingtin’s aggregation
The results suggest that the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice, and the emerging role of the first 17 amino acids of huntingtin in Huntington’s disease is underestimated.
Huntingtin and the Synapse
It is argued that wtHTT loss is not well-tolerated at the synaptic level, and it is concluded that wTHTT presence is essential for proper synaptic function.
Huntingtin-lowering strategies for Huntington’s disease
ABSTRACT Introduction Huntington’s disease (HD) is an incurable, autosomal dominant neurodegenerative disease caused by an abnormally long polyglutamine tract in the huntingtin protein. Because this
Huntingtin structure is orchestrated by HAP40 and shows a polyglutamine expansion-specific interaction with exon 1
The exon 1 region of HTT is dynamic but shows greater conformational variety in the polyglutamine expanded mutant than wildtype exon 2, and Native mass spectrometry reveals a remarkably stable hetero-dimer, potentially explaining the cellular inter-dependence ofHTT and HAP40.
HAP40 orchestrates huntingtin structure for differential interaction with polyglutamine expanded exon 1
The polyglutamine tract containing N-terminal exon 1 region of HTT is dynamic, but shows greater conformational variety in the mutant than wildtype exon 2, and Native mass-spectrometry reveals a remarkably stable hetero-dimer, potentially explaining the cellular inter-dependence ofHTT and HAP40.
Presynaptic protein synthesis and brain plasticity: From physiology to neuropathology
Here, a growing body of evidence is reviewed that local protein synthesis in discrete sites of the axon and presynaptic terminals plays crucial roles in synaptic plasticity, and that deregulation of this local translation system is implicated in various pathologies of the nervous system.
Blood-Brain Barrier Dysfunction in CNS Disorders and Putative Therapeutic Targets: An Overview
The fundamental structure and function of the blood-brain barrier is described in both healthy and altered/diseased conditions and the potential therapeutic targets that could be leveraged to restore the integrity of the BBB concomitant to the treatment of these brain disorders are provided.


Synuclein impairs trafficking and signaling of BDNF in a mouse model of Parkinson’s disease
The studies suggest that excessive ASYN likely alters endocytic pathways leading to axonal dysfunction in embryonic cortical neurons in PD mouse models and induces a significant increase in the activated levels of small Rab GTPases such as Rab5 and Rab7.
Huntingtin’s Function in Axonal Transport Is Conserved in Drosophila melanogaster
Drosophila melanogaster is validated as a model to study HTT function, and its dysfunction associated with HD, and results suggest that the function of HTT in axonal transport is conserved between flies and mammals.
The Biology of Huntingtin
This work reconsider the literature describing HTT-regulated molecular and cellular mechanisms that could be dysfunctional in HD and their possible physiological consequences for patients.
Genetic and pharmacological inhibition of calcineurin corrects the BDNF transport defect in Huntington's disease
The results validate calcineurin as a target for the treatment of HD and provide the first demonstration of the restoration of huntingtin function by an FDA-approved compound.
Tau Isoforms Imbalance Impairs the Axonal Transport of the Amyloid Precursor Protein in Human Neurons
It is found that perturbations in the endogenous balance of tau isoforms were sufficient to impair the transport of the Alzheimer's disease-related amyloid precursor protein (APP), although neuronal morphology was normal, and changes in 3R:4R tau ratio has an impact on the regulation of axonal transport and specifically in APP dynamics.
Huntingtin Controls Neurotrophic Support and Survival of Neurons by Enhancing BDNF Vesicular Transport along Microtubules
It is shown that huntingtin specifically enhances vesicular transport of brain-derived neurotrophic factor (BDNF) along microtubules, indicating that a key role of huntingtin is to promote BDNF transport and suggesting that loss of this function might contribute to pathogenesis.
Enhanced Sensitivity of Striatal Neurons to Axonal Transport Defects Induced by Mutant Huntingtin
It is found that movement of APP and BDNF is impaired in striatal and hippocampal, but not cortical, neurons from presymptomatic homozygous mutant mice carrying 150Q huntingtin knock-in mutations, which suggests that a loss of wild-type huntingtin function in fast axonal transport plays important roles in the development of cell-type-specific defects in HD.
TRiC subunits enhance BDNF axonal transport and rescue striatal atrophy in Huntington’s disease
It is shown that expression of mutant huntingtin (mHTT) induced defects in brain-derived neurotrophic factor (BDNF) transport in BACHD cortical axons that resulted in atrophy of striatal target neurons, and evidence that TRiC reagent-mediated reductions in mHTT enhanced BDNF delivery to restore the trophic status of BAC HD striatal neurons is found.
Phosphorylation of mutant huntingtin at S421 restores anterograde and retrograde transport in neurons.
It is shown that polyQ (polyglutamine)-htt is unable to promote transport of brain-derived neurotrophic factor (BDNF)-containing vesicles, but polyQ-htt constitutively phosphorylated at S421 is as effective as the wild-type (wt) as concerns transport of these vesicle.
Serine 421 regulates mutant huntingtin toxicity and clearance in mice.
It is found that S421 phosphorylation mitigates neurodegeneration by increasing proteasome-dependent turnover of m HTT and reducing the presence of a toxic mHTT conformer and offer in vivo validation for S421 as a therapeutic target in HD.