Lion's Mane and Progranulin: A Second Neurotrophic Pathway

Lion's Mane Neurotrophic Factors

ERK1/2 the signaling node shared by both hericerins and progranulin, creating a mechanistic hypothesis for a second lion's mane neurotrophic pathway

Martinez-Marmol and colleagues (2023) showed hericerin derivatives activate a pan-neurotrophic pathway converging on ERK1/2 signaling in hippocampal neurons. Van Damme and colleagues (2008) established that progranulin, a distinct neurotrophic factor, also signals through ERK1/2 independently of TrkA/B. The shared pathway creates a scientifically grounded hypothesis for a progranulin-related mechanism, though no study has directly tested it.

Martinez-Marmol et al., 2023; Van Damme et al., 2008

FTD-GRN

frontotemporal dementia caused by progranulin (GRN gene) mutations is one of the most common genetic causes of FTD; if lion's mane activates progranulin-related signaling, it would be mechanistically relevant to this disease

PI3K/Akt overlap

Chiu et al. (2018) showed erinacine A activates BDNF through PI3K/Akt/GSK-3β signaling, a pathway that overlaps with progranulin's downstream effects, providing another mechanistic connection point

No direct evidence

no published study has directly measured progranulin levels after lion's mane treatment; this article presents a scientifically grounded hypothesis, not an established finding

Martinez-Marmol et al., 2023; Van Damme et al., 2008

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The NGF story of lion's mane is well-established. Erinacines from the mycelium stimulate nerve growth factor production; NGF promotes neuron survival and new connection formation through the TrkA receptor. This is the mechanism that drives every "lion's mane improves memory" article.

What is less discussed is what happens when hericerins from the fruiting body activate ERK1/2 signaling in hippocampal neurons, as Martinez-Marmol and colleagues (2023) documented. ERK1/2 is not the endpoint of the NGF/TrkA pathway. It is a separate signaling hub that multiple neurotrophic factors converge on. Including progranulin, a neurotrophic factor with its own distinct biology that does not signal through TrkA or TrkB at all.

This article makes a hypothesis: lion's mane hericerins activate an ERK1/2 pathway that may include progranulin-related neurotrophic signaling. No study has directly tested this. The mechanistic case is scientifically grounded. For the established NGF story, see what is lion's mane mushroom: a science-based overview.

What Progranulin Is and Why It Matters for the Brain

Progranulin (encoded by the GRN gene, also called PGRN) is a secreted protein with multiple biological functions. In the nervous system, it functions as a neurotrophic factor: it promotes neurite outgrowth and neuronal survival, supporting the maintenance and growth of neural connections.

Van Damme and colleagues (2008) characterized progranulin's neurotrophic functions systematically, showing that it promotes neurite outgrowth and enhances neuronal survival through specific signaling cascades.^[2]

The key distinction from NGF: progranulin does not signal through TrkA (the NGF receptor) or TrkB (the BDNF receptor). These tyrosine kinase receptors are the entry points for the most studied neurotrophic factors. Progranulin's neurotrophic signaling runs through ERK1/2 and other pathways that it activates through different receptor interactions, including sortilin and TNFR. This means progranulin and NGF are mechanistically parallel: both promote neurite outgrowth and survival, but through different receptor binding and downstream pathways.

This distinction matters because it means you can have NGF-level neurotrophic support and still have progranulin deficiency, with corresponding deficits in the progranulin-dependent aspects of neuronal maintenance. The two pathways are additive, not redundant.

Why Progranulin Deficiency Causes Frontotemporal Dementia

Progranulin's clinical significance comes from FTD-GRN: frontotemporal dementia caused by loss-of-function mutations in the GRN gene. Frontotemporal dementia affects the frontal and temporal lobes of the brain, producing personality changes, language deficits, and executive function impairment rather than the memory-first presentation of Alzheimer's disease.

FTD-GRN is among the most common genetic causes of FTD, accounting for roughly 5-10% of all FTD cases. Patients with one dysfunctional GRN allele have roughly half-normal progranulin levels in cerebrospinal fluid and blood, and this reduced progranulin is sufficient to cause neurodegeneration over decades.

The mechanism: without adequate progranulin, neurons show accelerated lysosomal dysfunction (progranulin also regulates lysosomal biology), increased neuroinflammation (progranulin is anti-inflammatory in the brain), and reduced neurite maintenance. The neurodegeneration in FTD-GRN involves tau accumulation as well, making the FTD-progranulin connection relevant to tauopathies more broadly.

Rodriguez and colleagues (2022) tested lion's mane in the rTg4510 tau mouse model, which develops tau pathology relevant to FTD as well as Alzheimer's disease, and found anxiolytic effects alongside evidence of neuroprotection.^[6] The connection to progranulin is hypothetical, but the relevance to tau pathology and FTD-like biology is documented.

Martinez-Marmol 2023: The Pan-Neurotrophic ERK1/2 Pathway

Martinez-Marmol and colleagues (2023) made the specific finding that motivates this article: hericerin derivatives from lion's mane fruiting body activate a pan-neurotrophic pathway converging on ERK1/2 in hippocampal neurons, independent of TrkB.^[1]

The "pan-neurotrophic" description means the pathway activates signaling for multiple neurotrophic factors simultaneously (NGF, BDNF, and NT-3, as the study documented) through the common ERK1/2 convergence point. The "independent of TrkB" specification means this is not simply BDNF's standard receptor pathway: hericerins are accessing ERK1/2 through a route that doesn't require the classical TrkB binding.

ERK1/2 is a convergence point for multiple upstream signaling cascades. TrkA (NGF), TrkB (BDNF), progranulin signaling, and multiple other growth factor pathways all activate ERK1/2 among their downstream effects. When hericerins activate ERK1/2 through a TrkB-independent route, they are engaging a signaling hub that sits downstream of these multiple upstream pathways.

The hypothesis this creates: if hericerins activate the ERK1/2 convergence point through a broad upstream signal, that activation might engage downstream effectors that are shared with progranulin signaling. Alternatively, the upstream receptor that hericerins use to access ERK1/2 might overlap with progranulin's receptor systems. The specific mechanism through which hericerins access ERK1/2 has not been fully characterized, leaving the progranulin connection as a mechanistically plausible but untested hypothesis.

The PI3K/Akt Overlap: Chiu 2018

The case for a progranulin connection is reinforced by Chiu and colleagues' (2018) finding that erinacine A activates BDNF through the PI3K/Akt/GSK-3β signaling pathway in mice.^[3]

PI3K/Akt signaling is a downstream target of progranulin. When progranulin binds to sortilin or signals through other receptors, PI3K activation is one of the downstream consequences. The fact that erinacine A activates PI3K/Akt (through BDNF induction) means lion's mane compounds are engaging a pathway that progranulin also engages.

This is not direct evidence that erinacine A increases progranulin. It is evidence that lion's mane compounds and progranulin share downstream signaling territory. A compound that raises BDNF (which then activates PI3K/Akt) and a neurotrophic factor that directly activates PI3K/Akt are not doing the same thing, but they are producing overlapping effects on the same downstream pathway. The clinical significance of this overlap is unknown because no study has measured progranulin levels or progranulin-dependent endpoints in lion's mane treatment conditions.

The Emerging Epigenetic Framework

Cipriano and colleagues (2026) proposed a broader model for how H. erinaceus bioactives produce their neurotrophic effects: a neurotrophic-epigenetic axis involving non-coding RNA networks that regulate which neurotrophic genes are expressed.^[4]

This hypothesis suggests that hericerins and erinacines may influence gene expression broadly through epigenetic regulation (changes in which genes are accessible for transcription) rather than only through direct receptor binding. If this is the mechanism, the set of neurotrophic factors whose gene expression lion's mane modulates could be broader than the NGF, BDNF, and NT-3 specifically documented in the Martinez-Marmol 2023 study.

Progranulin is encoded by the GRN gene. If lion's mane bioactives regulate gene expression epigenetically in a manner that affects GRN transcription, progranulin levels could be affected upstream of any receptor-based mechanism. This is a second pathway through which the progranulin hypothesis could operate. Both the Cipriano 2026 epigenetic model and the direct ERK1/2 pathway model remain hypotheses pending direct experimental testing.

Spangenberg and colleagues (2025) published a systematic review of erinacines' neuroprotective effects in preclinical models, providing the current authoritative summary of what the erinacine evidence base has established and where the gaps remain.^[5] Progranulin-specific testing is among the gaps the field has not yet addressed.

What Would Confirm the Hypothesis

The progranulin hypothesis would be confirmed or refuted by direct experimental testing: treating animals or cells with lion's mane compounds (specifically hericerins, given their ERK1/2 activation) and measuring progranulin protein levels and GRN mRNA expression in neural tissue.

Testing in a GRN haploinsufficient mouse model (which models FTD-GRN by having half-normal progranulin) would provide the most clinically relevant test: does lion's mane treatment rescue any of the neurological deficits associated with progranulin deficiency?

These experiments have not been published. The hypothesis has mechanistic grounding and would be straightforward to test in existing models. Until those experiments are conducted, the progranulin connection remains a scientifically interesting possibility rather than an established finding.

The Bottom Line

Martinez-Marmol 2023 showed hericerins activate pan-neurotrophic ERK1/2 signaling independently of TrkB. Van Damme 2008 established progranulin as a neurotrophic factor that also signals through ERK1/2, not TrkA/B. The shared ERK1/2 convergence creates a hypothesis for progranulin-related signaling from lion's mane, reinforced by Chiu 2018's PI3K/Akt overlap and Cipriano 2026's epigenetic axis hypothesis. The clinical relevance is FTD-GRN, where progranulin deficiency causes frontotemporal dementia. No published study has directly measured progranulin levels after lion's mane treatment; this remains an unconfirmed hypothesis.

Frequently Asked Questions

What is progranulin in the brain?

Progranulin (encoded by the GRN gene) is a secreted protein that functions as a neurotrophic factor in the nervous system. It promotes neurite outgrowth and neuronal survival through ERK1/2 signaling, distinct from NGF's TrkA pathway. It also regulates lysosomal function and has anti-inflammatory effects in the brain. Deficiency caused by GRN gene mutations causes frontotemporal dementia (FTD-GRN), one of the most common genetic forms of FTD.

How is progranulin different from NGF?

They are both neurotrophic factors that promote neuron survival and growth, but through different receptors and pathways. NGF binds TrkA (tyrosine receptor kinase A) to activate downstream signaling. Progranulin signals through sortilin, TNFR, and other receptors, activating ERK1/2 and PI3K/Akt through TrkA-independent routes. This means progranulin and NGF provide parallel but non-redundant neurotrophic support; deficiency in one cannot be compensated by the other.

What disease is caused by progranulin deficiency?

Frontotemporal dementia with progranulin mutations (FTD-GRN). Loss-of-function mutations in one GRN allele reduce progranulin to roughly half normal levels, causing neurodegeneration in the frontal and temporal lobes over decades. FTD-GRN accounts for approximately 5-10% of all FTD cases and involves tau accumulation alongside lysosomal dysfunction and neuroinflammation. It is distinct from Alzheimer's disease in its clinical presentation and pathology.

Does lion's mane affect neurotrophic factors beyond NGF?

Yes, with established evidence for some and hypothesis for others. Martinez-Marmol 2023 confirmed that hericerins activate NGF, BDNF, and NT-3 simultaneously through a pan-neurotrophic ERK1/2 pathway. Chiu 2018 showed erinacine A raises BDNF through PI3K/Akt signaling. The progranulin connection is hypothetical: lion's mane hericerins activate ERK1/2 and PI3K/Akt pathways that progranulin also engages, but no study has directly measured progranulin levels after lion's mane treatment.

What other neurotrophic factors does lion's mane increase?

Directly documented: NGF (erinacines via TrkA-downstream NGF induction), BDNF (erinacine A via PI3K/Akt; hericerins via ERK1/2), NT-3 (hericerins via ERK1/2, per Martinez-Marmol 2023). Hypothetically relevant: progranulin (through shared ERK1/2 and PI3K/Akt signaling, not yet directly measured). Cipriano 2026 proposed that epigenetic regulation via non-coding RNA networks could affect neurotrophic gene expression more broadly.

Sources & References

1. 1RTHM-01746·Martínez-Mármol, Ramón et al. (2023). “Hericerin derivatives activates a pan-neurotrophic pathway in central hippocampal neurons converging to ERK1/2 signaling enhancing spatial memory..” Journal of neurochemistry.Study breakdown →PubMed →↩
2. 2RTHM-00279·Van Damme, Philip et al. (2008). “Progranulin functions as a neurotrophic factor to regulate neurite outgrowth and enhance neuronal survival..” The Journal of cell biology.Study breakdown →PubMed →↩
3. 3RTHM-00505·Chiu, Chun-Hung et al. (2018). “Erinacine A-Enriched Hericium erinaceus Mycelium Produces Antidepressant-Like Effects through Modulating BDNF/PI3K/Akt/GSK-3β Signaling in Mice..” International journal of molecular sciences.Study breakdown →PubMed →↩
4. 4RTHM-02226·Cipriano, Giovanni Luca et al. (2026). “Beyond Neurotrophins: A Proposed Neurotrophic-Epigenetic Axis Mediated by Non-Coding RNA Networks for Hericium erinaceus Bioactives-A Hypothesis-Driven Review..” International journal of molecular sciences.Study breakdown →PubMed →↩
5. 5RTHM-02184·Spangenberg, E T et al. (2025). “Unveiling the role of erinacines in the neuroprotective effects of Hericium erinaceus: a systematic review in preclinical models..” Frontiers in pharmacology.Study breakdown →PubMed →↩
6. 6RTHM-01610·Rodriguez, Mya N et al. (2022). “Lion's Mane (Hericium erinaceus) Exerts Anxiolytic Effects in the rTg4510 Tau Mouse Model..” Behavioral sciences (Basel.Study breakdown →PubMed →↩