Pathway Activation Clears Signs of Huntington’s in Mouse Model: Study

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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Huntington's disease astrocytes | Huntington's Disease News | illustration of a mouse model

Activating the JAK2-STAT3 pathway in astrocyte cells reduced multiple hallmark features of Huntington’s disease  — including the toxic clumping of the huntingtin protein in nerve cells — from the brains of a mouse model, a study reported.

“Our results open new therapeutic avenues to further enhance the natural partnership between reactive astrocytes and vulnerable neurons in Huntington’s disease,” the scientists wrote.

The study, “Reactive astrocytes promote proteostasis in Huntington’s disease through the JAK2-STAT3 pathway,” was published in Brain.

In Huntington’s, a faulty HTT gene leads to the production of an abnormally long huntingtin protein, which is thought to form aggregates or clumps in the brain, causing damage to nerve cells (neurons), but also other types of cells that support neurons called glial cells.

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human cell model | Huntington's Disease News | illustration of cells in petri dish

Huntington’s Protein Clumps Form Distinct Structures in Nerve Cells

Astrocytes are specialized star-shaped glial cells in the brain that are essential partners of neurons, performing many key functions, including metabolic support and responding to neuron injury. Most studies report impaired astrocyte functions in Huntington’s disease that involve structural, molecular, and functional changes.

However, because Huntington’s disease mouse models poorly replicate the reactive state of astrocytes seen in the brain of Huntington’s patients, the impact of reactive astrocytes on disease progression remains unclear.

The signaling pathway known as JAK2-STAT3 is activated in reactive astrocytes of mice and non-human primate models of Huntington’s disease. It’s unknown whether this pathway is activated in reactive astrocytes in patients’ brains and whether it controls astrocyte function.

Recently, researchers at the Université Paris-Saclay, France found that blocking the JAK2-STAT3 pathway in reactive astrocytes in a Huntington’s model reduced their reactive characteristics and increased the number of mutant huntingtin protein (mHTT) aggregates.

In this report, the team investigated this pathway in Huntington’s disease patients and in two complementary mouse models.

STAT3 protein staining of Huntington’s disease patients’ postmortem brain samples revealed strong signals for STAT3, especially in areas of the brain that showed degeneration, compared to age- and sex-matched controls. Many cells with STAT3 had a typical astrocyte structure and an increase of STAT3 in the nucleus, indicating pathway activation.

“These results support a role for STAT3 in driving astrocyte reactive changes in Huntington’s disease,” the researchers wrote.

The pathway was then activated in astrocytes in Hdh140 mice bred to produce a human version of the faulty HTT gene. This mouse model develops Huntington’s with very mild structural and molecular changes in astrocytes. The JAK2 protein was selectively activated in astrocytes from the striatum — a brain region involved in movement and particularly affected in Huntington’s.

Tissue analysis showed increased JAK2 significantly reduced the total number and size of mHTT aggregates in the striatum, but not in the distribution of aggregates in different astrocyte subsets.

Further examination found JAK2-STAT3 pathway activation reduced tissue shrinkage in the striatum and increased levels of the nerve cell signaling molecule glutamate, two hallmark features of Huntington’s disease.

In a second mouse model that also carries a defective HTT gene, but better replicates the substantial degeneration and astrocyte reactivity observed in patients, blocking the JAK2-STAT3 pathway in astrocytes increased mHTT aggregation in neurons and significantly increased striatal lesion volume.

Genetic analysis showed increased JAK2 in striatal astrocytes of healthy and Hdh140 mice activated genes associated with proteostasis — a balancing of biological pathways that control the production and degradation of proteins within and outside the cell.

Activating the JAK2-STAT3 pathway in astrocytes also activated genes associated with the increased capacity to break down aggregated proteins.

To directly measure the intrinsic capacity of astrocytes to clear aggregates, mHTT production was stimulated in the right side striatum in healthy mice, which triggered STAT3 activation and induced astrocyte changes. Blocking the JAK2-STAT3 pathway increased the total number and size of mHTT aggregates, showing that “the JAK2-STAT3 pathway stimulates astrocyte intrinsic capacity for mHTT clearance,” the researchers wrote.

Lastly, activated JAK2 significantly increased the DNAJB1 chaperone protein level and its release in the striatum of Hdh140 mice. DNJAB1, which aids other proteins to fold properly to prevent aggregate formation, helped clear the aggregates in neurons.

“We show that the JAK2-STAT3 pathway activates a beneficial proteostasis program in reactive astrocytes, which helps striatal neurons handle toxic mHTT,” the authors concluded. “Astrocytes are not only defective in Huntington’s disease as usually reported, they may also acquire enhanced capacities to promote mHTT clearance and neuronal functions.”