Research Summaries & Highlights
A neuron subtype-specific role of MEK-ERK signaling in axon survival via transcriptional regulation of NMNAT2
The MAPK pathway, of which MEK and ERK are members, is important for signaling and regulating which genes are expressed. Trametinib is a MEK inhibitor used to treat cancer, but it causes lesions and degeneration in neurons outside of the brain and spinal cord (peripheral nerves). Interestingly, nerves from the spinal cord and brain (the central nervous system) seemed to be protected by trametinib, showing that context is really important for determining the effects of stress on neuron health. The authors found that when peripheral nerves were treated with trametinib, their expression of the protein NMNAT2 was significantly decreased. NMNAT2 is important because it helps make NAD+, which is necessary for cellular metabolism and for preventing SARM1 activation. By overexpressing NMNAT2, the authors were able to reverse the neurodegenerative effects of trametinib.
https://www.cell.com/cell-reports/fulltext/S2211-1247(26)00009-4
Systematic analysis of cellular cross-talk reveals a role for SEMA6D-TREM2 regulating microglial function in Alzheimer’s disease
The authors isolated nuclei from 67 post-mortem brains and then sequenced the RNA from them. From this, they were able to predict thousands of cell-cell communication interactions, and found that there was extensive communication between neurons and microglia (the resident immune cells of the brain). This communication appeared to be disrupted in the brains of Alzheimer’s patients. They showed that TREM2 is a hub for this communication, and that a protein called SEMA6D is a key signaling partner for the activation of microglia. This communication is helpful for clearing amyloid-beta plaques, so its disruption in Alzheimer’s helps explain the build of plaques seen in patients.
https://pubmed.ncbi.nlm.nih.gov/40737431/
Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson’s disease
The authors investigated the role of the FAM171A2 gene in alpha-synuclein aggregation and uptake in Parkinson’s disease. First, they found significantly increased FAM171A2 expression in the post-mortem midbrain tissue of patients with Parkinson’s. Overexpression of FAM171A2 increased the level of aggregation prone alpha-synuclein in dopaminergic neurons, while knockdown of FAM171A2 rescued this accumulation. The authors showed that FAM171A2 helps alpha-synuclein enter cells through a process called endocytosis, and that in fact they directly bind together. Using computer modeling, they found seven FDA-approved compounds that were predicted to prevent their binding. Bemcentinib, one of the seven, prevented alpha-synuclein from entering neurons both in cultured cells and in mice.
https://pubmed.ncbi.nlm.nih.gov/39977508/
Foldamers rescue synucleinopathy phenotypes in multiple in vitro and in vivo models
Foldamers are synthetic molecules that spontaneously fold into specific shapes when in solution. Here, the authors used a foldamer called SK-129 to bind to alpha-synuclein aggregates. In Parkinson’s models of both worms and cultured human neurons, treatment with SK-129 improved many hallmarks of disease including number of dopaminergic neurons and ROS levels. In cells, alpha-synuclein aggregates from diseased cells can spread to healthy cells in sacs called exosomes. When cells were treated with SK-129, exosomes contained fewer aggregates, and the spread of aggregation was lowered. Finally, the authors treated a mouse Parkinson’s model with SK-129, and they found that the treated mice survived and retained their body weight, while the untreated mice did not.
https://pubmed.ncbi.nlm.nih.gov/41920967/
Lowering the HTT1a transcript as an effective therapy for Huntington’s disease in a knockin mouse model
Huntington’s disease is caused by a CAG repeat expansion in the huntingtin gene (HTT), and the more repeats there are the earlier onset the disease is. When the repeat is expanded, a more aggregation prone and pathogenic version of the protein can be made called HTT1a. The authors identified an siRNA (small interfering RNA that prevents the protein from being made) targeting the HTT transcript, and two siRNAs they used in combination to target the HTT1a transcript. They tested the levels of both full length HTT and HTT1a in the hippocampus of mice following treatment to confirm that it had the desired effect. They also imaged the brain to see the effect of targeting either transcript on nuclear HTT aggregation. This showed that specifically targeting HTT1a led to significantly less aggregation. They also showed that the disease-associated changes in gene regulation were reversed when HTT1a was targeted, but not when full length HTT was targeted.
https://pubmed.ncbi.nlm.nih.gov/41849583/
In silico screening and preclinical validation identify bavisant as a therapeutic candidate for multiple sclerosis
The authors wanted to discover new drugs that promote a process called remyelination (think of myelin as the rubber that insulates the neuron to help it carry its signal) in multiple sclerosis (MS). They started with 1500 compounds and used a combination of computer modeling, cell toxicity tests, and functional tests to identify top candidates from the list. The best of these, bavisant, was tested both in cell culture and in multiple mouse models of MS. The authors found that bavisant successfully promoted remyelination, reduced axon degeneration, and preserved neuronal structure.
https://pubmed.ncbi.nlm.nih.gov/41564155/
Brain-derived tau for monitoring brain injury in acute ischemic stroke
Finding better and less invasive biomarkers for neurodegenerative diseases is crucial to detecting disease earlier, tracking progression more thoroughly, and assessing how well therapies work. This study identified brain derived tau (BD-tau) in blood as a new biomarker for tracking ischemic stroke progression and severity. BD-tau levels in blood correlated with infarct volume (volume of tissue that died from lack of oxygen). Higher levels also were associated with worse 3-month, 12-month, and 36-month outcomes, more so than CT scans of the infarct area in fact. This shows BD-tau could be one of the most valuable markers doctors can look at during a stroke.
https://pubmed.ncbi.nlm.nih.gov/41533774/
LRRK2 regulates production of reactive oxygen species in cell and animal models of Parkinson’s disease
Oxidative stress has been implicated in Parkinson's pathogenesis, but where it comes from and how its regulated remains an open question. Mutations in leucine rich repeat kinase 2 are associated with PD. Overexpression of mutant LRRK2 is associated with oxidative stress, and this toxicity can be rescued with antioxidants. Elevated LRRK2 activity from disease-associated mutations is associated with more ROS and lipid peroxidation, and this seems to happen by over activating a protein called NADPH oxidase 2 (NOX2). Inhibitors of LRRK2 kinase blocks this increase in ROS. Rotenone, a mitochondrial toxin, induced oxidative stress is fixed when LRRK2 kinase is inhibited or when LRRK2 was knocked out. In models of PD, LRRK2 kinase inhibition prevented lipid peroxidation and NOX2 activation.
https://pubmed.ncbi.nlm.nih.gov/39356746/