How do GP-DPRs activate MAPK signaling to disrupt axonal transport and synaptic function?

OPEN

The study identifies MAPK pathway involvement in GP-DPR toxicity but doesn't explain the molecular mechanism linking GP-DPRs to MAPK activation. Understanding this pathway is critical for developing targeted therapeutics for C9ORF72-ALS/FTD. Gap type: unexplained_observation Source paper: Divergent Molecular Pathways for Toxicity of Selected Mutant C9ORF72-derived Dipeptide Repeats. (None, None, PMID:37808871)

Priority: 0.82 Domain: neurodegeneration Hypotheses: 0

📊 Landscape Analysis

Landscape Summary: How do GP-DPRs activate MAPK signaling to disrupt axonal transport and synaptic function? is a 0.82 priority gap in neurodegeneration. It has 0 linked hypotheses with average composite score 0.000. Status: open.

Key Unanswered Questions

What is the optimal TREM2 modulation strategy across disease stages?
How does DAM activation state affect therapeutic outcomes?
What biomarkers predict response to TREM2-targeted interventions?

Key Researchers

Colonna, Sevlever, et al. (TREM2 biology)

Clinical Trials

How do GP-DPRs activate MAPK signaling to disrupt axonal transport and synaptic function? — INVOKE-2 (completed)

📈 Living Dashboards

0

Hypotheses

0.000

Top Score

0.000

Avg Score

0

Debates

0.00

Avg Quality

0%

Resolution

0

Mechanistic Families

Gap Resolution Progress0%

Hypothesis Score Distribution

🏆 Competing Hypotheses (Ranked by Score)

No hypotheses linked to this gap yet.

🌊 Knowledge Graph Connections

activates (13)

MTOR→MAPKPI3K→MAPKMASP1→MAPKCD97→MAPKMAPK→Mitochondrial Fission

▸ Show 8 more

KRAS→MAPKTMPC-ANXA2 Interaction→MAPKMAPK→ADIPOR1MAP2K1→MAPKCHOLIX→MAPKIGF1R→MAPKLPS→MAPKAKT→MAPK

associated with (15)

AKT→MAPKAMYLOID→MAPKALZHEIMER'S DISEASE→MAPKNF-KB→MAPKMICROGLIA→MAPK

▸ Show 10 more

TNF→MAPKERK→MAPKPARKINSON'S DISEASE→MAPKMAPK→gastric cancerMAPK→colitis-associated colorectal cancerJNK→MAPKMAPK→liver fibrosisIL-6→MAPKMTOR→MAPKTAU→MAPK

drives (1)

expressed in (1)

inhibits (6)

Trametinib→MAPKBEST3→MAPKpaeoniflorin→MAPKginseng root extract→MAPKgallic acid→MAPK

▸ Show 1 more

MAPK→neuroinflammation

participates in (6)

MAPK→oxidative stress responseMAPK→ubiquitin-proteasomeMAPK→NF-kB signalingMAPK→unfolded protein responseMAPK→PI3K-AKT-mTOR signaling

▸ Show 1 more

MAPK→MAPK signaling

phosphorylates (2)

MAPK→TDP-43MAPK→DRP1

promotes (2)

MAPK→metastasisMAPK→oxidative stress

regulates (2)

MAPK→cellular proliferationMAPK→cell migration

upstream of (2)

MAPK→ATF2p38→MAPK

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