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How does constitutive lysosomal TBK1 accumulation in ALS-FTD mutants cause neurodegeneration?

OPEN

The E696K TBK1 mutant shows constitutive lysosomal accumulation and elevated mTORC1 activation, but the causal link to ALS-FTD pathogenesis remains unclear. This mechanistic gap is critical for understanding disease progression and developing targeted therapies. Gap type: unexplained_observation Source paper: Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition. (2024, The EMBO journal, PMID:39103493)

Priority: 0.85 Domain: neurodegeneration Hypotheses: 0
📊 Landscape Analysis

Landscape Summary: How does constitutive lysosomal TBK1 accumulation in ALS-FTD mutants cause neurodegeneration? is a 0.85 priority gap in neurodegeneration. It has 0 linked hypotheses with average composite score 0.000. Status: open.

Key Unanswered Questions

Key Researchers

Colonna, Sevlever, et al. (TREM2 biology)

Clinical Trials

How does constitutive lysosomal TBK1 accumulation in ALS-FTD mutants cause neurodegeneration? — 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)

TBK1→Immune ResponseTBK1→CGASTBK1→IRF3TBK1→CGAS-STINGTBK1→Als
▸ Show 8 more

associated with (8)

TBK1→AlsTBK1→Frontotemporal DementiaLoss Of TDP-43 Splicing Repression→ALS-FTDTDP-43→ALS-FTDTBK1→Amyotrophic Lateral Sclerosis
▸ Show 3 more

binds (1)

TBK1→Optineurin

biomarker for (1)

Cryptic HDGFL2→ALS-FTD

causes (4)

TBK1→Motoneuron pathologyTBK1→alsTBK1→Autophagolysosomal dysfunctionCytoplasmic TDP-43 Aggregation→ALS-FTD

contributes to (1)

TBK1→Autophagolysosomal Dysfunction

describes (1)

genes-tbak1→TBK1

does not cause (1)

TBK1→neuroinflammation

encodes (1)

TBK1→TBK1

implicated in (1)

TBK1→amyotrophic lateral sclerosis

inhibits (2)

amlexanox→TBK1FIP200→TBK1

interacts with (3)

AUTOPHAGY→TBK1TBK1→AlsZBP1→TBK1

linked to (1)

genes-tbk1→TBK1

phosphorylates (3)

TBK1→Sqstm1TBK1→CALCOCO2TBK1→p62

regulates (4)

TBK1→selective autophagyTBK1→autophagy pathwayTBK1→innate immunityTBK1→macroautophagy

risk factor for (5)

TBK1→amyotrophic lateral sclerosisC9ORF72→ALS-FTDTBK1→ALSTBK1→ALS/FTDTBK1→FTD
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