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Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Nature Reviews Drug Discovery volume 10, pages 853–867 (2011)Cite this article

Subjects

Key Points

  • Although their aetiology is different, neurodegenerative diseases such as Alzheimer's disease and Huntington's disease have remarkable similarities at the level of molecular pathogenic processes. These shared pathways contain common therapeutic targets that could be exploited for drug development.

  • These shared pathogenic pathways include: the aberrant phosphorylation, palmitoylation and acetylation of disease-causing proteins; protein misfolding; a failure to clear disease-causing proteins by the ubiquitin–proteasome system or autophagy; changes in NMDA (N-methyl-D-aspartate) receptor activity at the synapse; alterations in the levels of brain-derived neurotrophic factor and nerve growth factor as well as associated receptors and trafficking pathways; and increased activity of caspase enzymes.

  • Not all targets are validated to the same degree in Alzheimer's disease and Huntington's disease; here, we provide a framework for ranking and direct comparison to identify the knowledge gaps that exist. This information should encourage greater interaction between scientists in the HD and AD research communities.

  • The inherited aetiology of Huntington's disease allows for the identification of individuals who carry the mutation but do not manifest symptoms, and early clinical changes in this population are currently being tracked. This knowledge will allow accurate clinical trials to be carried out to assess the disease-modifying properties of therapeutics at early stages of the illness.

  • Novel therapeutics could be assessed in a well-defined population of patients with Huntington's disease to provide early proof of concept for the modulation of pathways that are perturbed in both Alzheimer's disease and Huntington's disease. These results could then serve to prioritize testing in a more heterogeneous population of patients with Alzheimer's disease, for whom clinical end points and longitudinal markers of disease progression are not defined in as much detail.

Abstract

Neurodegenerative diseases, exemplified by Alzheimer's disease and Huntington's disease, are characterized by progressive neuropsychiatric dysfunction and loss of specific neuronal subtypes. Although there are differences in the exact sites of pathology, and the clinical profiles of these two conditions only partially overlap, considerable similarities in disease mechanisms and pathogenic pathways can be observed. These shared mechanisms raise the possibility of exploiting common therapeutic targets for drug development. As Huntington's disease has a monogenic cause, it is possible to accurately identify individuals who carry the Huntington's disease mutation but do not yet manifest symptoms. These individuals could act as a model for Alzheimer's disease to test therapeutic interventions that target shared pathogenic pathways.

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Figure 1: Therapeutic targets in the synaptic dysfunction pathway.
Figure 2: Therapeutic targets in the neurotrophin pathway.
Figure 3: Therapeutic targets in the apoptotic pathway.
Figure 4: Therapeutic targets in the protein misfolding pathway.
Figure 5: Therapeutic targets in the autophagy pathway.

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Acknowledgements

The authors would like to thank W. Song and B. Leavitt for their comments on this article.

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Authors and Affiliations

  1. Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child & Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, V5Z 4H4, British Columbia, Canada

    Dagmar E. Ehrnhoefer, Bibiana K. Y. Wong & Michael R. Hayden

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  1. Dagmar E. Ehrnhoefer
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Supplementary information

Supplementary information S1 (table)

Synaptic targets and targets in neurotrophin signalling (PDF 182 kb)

Supplementary information S2 (table)

Targets in the apoptotic pathway (PDF 178 kb)

Supplementary information S3 (table)

Targets in posttranslational modifications (PDF 175 kb)

Supplementary information S4 (table)

Targets in aggregation and clearance pathways (PDF 180 kb)

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FURTHER INFORMATION

Michael Hayden's homepage

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Glossary

Chorea

An abnormal involuntary movement such as an irregular, rapid, involuntary or excessive movement, which seems to randomly affect different parts of the body. A characteristic feature of Huntington's disease.

Dementia

A gradual decline in mental ability that affects intellectual skills such as memory, concentration and judgement. It is sometimes accompanied by emotional disturbances and changes in personality.

Microtubule

One of the principal components of the cytoskeleton. Microtubules are hollow, dynamic rod structures that participate in determining cell shape, cell locomotion and intracellular transport processes.

CAG repeat

A trinucleotide repeat of cytosine, adenine and guanine (CAG) that results in the expression of a chain of glutamines in the protein sequence.

Polyglutamine tract

The part of a protein that is entirely composed of the amino acid glutamine, resulting from a cytosine, adenine and guanine (CAG) repeat in the corresponding gene.

Medium spiny neurons

A type of GABA (γ-aminobutyric acid)-ergic inhibitory neurons that have a key role in movement initiation and control. They represent ∼90% of the neurons in the striatum of the brain.

CA1 zone

Cornu ammonis area 1. An area of the hippocampus that is composed of densely packed pyramidal cells.

Entorhinal cortex

An area located in the medial temporal lobe of the brain. Neurons from this area project to the hippocampus. The entorhinal cortex is involved in memory formation, in particular spatial memory.

Ubiquitin–proteasome system

A major pathway for the intracellular degradation of proteins. Substrates are conjugated to the peptide ubiquitin and transported to the proteasome, an organelle that has proteolytic activity and breaks the polypeptide chain into single amino acids.

Neurotrophic factor

A peptide secreted by brain tissues to guide axonal growth that is responsible for neuronal growth, differentiation and survival.

Synaptic plasticity

A process involved in learning and memory, whereby synapses gauge the intensity of their response to an incoming signal. It occurs as a result of the modulation of the number or sensitivity of receptors at the synapse or changes in the quantity of neurotransmitters released.

Morris water maze

An experiment that is used to assess spatial learning and memory in rodents. Rodents are placed in a circular pool of water, and by learning spatial markers they can identify the location of a hidden platform and escape from the water.

Microglia

Resident macrophages of the central nervous system that initiate immune responses and inflammation in the brain.

Excitotoxicity

A pathological process that is mediated through excessive stimulation of NMDA (N-methyl-D-aspartate) receptors by glutamate or other agonists. Increased activation of these receptors leads to a massive influx of calcium, which activates pro-death signalling pathways.

Caspase 6

A member of the cysteine-aspartic protease (caspase) family that has essential roles in programmed cell death (apoptosis).

Apoptotic cell death

Also known as programmed cell death. A mechanism of removing superfluous or damaged cells without eliciting an inflammatory response. It occurs during development and following chronic or acute cell and tissue damage.

Developmental pruning

A change in neuronal structure during development that removes unnecessary neurons or neuronal connections.

Post-translational modification

A biochemical change made to a protein after the synthesis of the polypeptide chain is complete. This can include the attachment of lipids, carbohydrates, other small chemical entities (such as phosphate or acetate groups) or peptides (such as ubiquitin or small ubiquitin-related modifier), as well as the proteolytic cleavage of precursor proteins into functional fragments.

Macroautophagy

The second major degradation pathway that can be used to degrade proteins, protein aggregates and entire organelles. Substrates are engulfed by vesicles (autophagosomes) that later fuse with lysosomal vesicles that have proteolytic activity. Degradation occurs in the final autophagolysosome.

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Ehrnhoefer, D., Wong, B. & Hayden, M. Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development. Nat Rev Drug Discov 10, 853–867 (2011). https://doi.org/10.1038/nrd3556

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