Zhang H, Knight C, Chen SR, Bezprozvanny I. A Gating Mutation in Ryanodine Receptor Type 2 Rescues Phenotypes of Alzheimer's Disease Mouse Models by Upregulating Neuronal Autophagy. J Neurosci. 2023 Feb 22;43(8):1441-1454. Epub 2023 Jan 10 PubMed.

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  1. Besides canonical anatomical lesions linked to Aβ peptides and hyperphosphorylated tau protein, Alzheimer’s disease is also characterized by several other dysfunctions, including in Ca2+ signaling and mitophagic/autophagic function. Although it is well documented that autophagy could be modulated by intracellular calcium, the mechanistic link remained unclear. In these two papers, the teams of Ilya Bezprozvanny and Grace Stutzmann identified the Ryanodine receptor (RyR) as the center of gravity in an interplay between intracellular calcium deficits and lysosomal/autophagic function.

    The two articles nicely used distinct complementary state-of-the-art approaches. Bezprozvanny and colleagues showed that basal hippocampal RyR2 activity inhibited autophagy by a calcineurin- and AMPK-dependent cascade. They used knock-in mice, in which an activity-deficient RyR was expressed, that they crossed with an AD model displaying exacerbated amyloid-related stigmata. Interestingly, reduction of RyR rescued Aβ accumulation and abrogated synaptic plasticity defects.

    In Stutzmann et al., by means of fluorescent biosensors and optical imaging, they similarly conclude on the involvement of the RyR. In neurons derived from AD patients, it associated with a reduction of the lysosomal proton pump vacuolar ATPase expression and, thereby, with exacerbated proteinopathy due to impaired autophagic clearance.

    Of most interest, the negative allosteric modulator of the RyR, dantrolene, restored lysosomal acidification and autophagic clearance of intracellular protein aggregates in animal models of AD, as well as in iPSC-derived neurons from AD patients.

    Overall, both studies concur in suggesting an overactivation of RyR in AD and identifying a possible pharmacological means to circumscribe autophagic defects and associated protein accumulation. This agrees well with our previous work showing that, in murine models of AD, an endoplasmic reticulum calcium leak was observed that could be accounted for by Ryanodine receptor post-translational remodeling and that pharmacological stabilization of RyR or genetic rescue could reverse synaptic plasticity alterations and normalize AD-linked cognitive defects (Lacampagne et al., 2017). 

    The two recent papers describe very well-designed studies with complementary approaches raising similar conclusions. These represent a huge step toward a better understanding of the phenotypic alterations linking Ca2+ signaling perturbation and autophagic processes. Besides AD, this molecular cascade and its dysfunction could well account for process taking place more generally in other brain proteinopathies.

    References:

    Lacampagne A, Liu X, Reiken S, Bussiere R, Meli AC, Lauritzen I, Teich AF, Zalk R, Saint N, Arancio O, Bauer C, Duprat F, Briggs CA, Chakroborty S, Stutzmann GE, Shelanski ML, Checler F, Chami M, Marks AR. Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer's disease-like pathologies and cognitive deficits. Acta Neuropathol. 2017 Nov;134(5):749-767. Epub 2017 Jun 19 PubMed.

    View all comments by Frédéric Checler

  2. It was very interesting to read these two papers which, for the first time, link increased RyR2-induced calcium release from the ER with endosomal-autophagic-lysosomal (EAL) defects in AD. Both the RyR2 and EAL systems become aberrant at very early stages of AD, preceding the development of Aβ and tau pathogenesis. These results present the exciting prospect that “normalizing” increased activation of RyR2 Ca2+ release in AD neurons could ameliorate defects in EAL systems.

    It's been more than 20 years since we discovered defective and increased RyR2 activity in brains of people who had sporadic AD (Kelliher et al., 1999). Since then discoveries from these teams, and others, have highlighted hyperactivation of RyR2, and Ca2+ homeostasis defects, as early events that can be targeted to prevent AD pathogenesis and cognitive decline, and now we can add the EAL system to this list.

    What do these studies mean for understanding and potentially targeting the RyR2/EAL system to ameliorate AD? Both papers focus on Familial AD (FAD) mouse models, providing novel data, but making the results difficult to interpret with respect to sporadic AD. Mustaly-Kalimi et al. employ human iPSC-derived neurons from AD patients with the A246E PS-1 FAD mutation, importantly revealing translation to human neurons. It would help substantially to determine whether key components of RyR-2-EAL dysfunction described in both papers—reduced vATPase subunits, lysosomal acidity, calcineurin-AMPK-ULK1 pathway and EAL defects—translate to iPSC-derived human neurons from sporadic AD patients or to human iPSC neurons expressing sporadic AD risk genes such as APOE-ε4. Furthermore, determining how these EAL systems link to aberrant RyR2 in the postmortem brains of individuals who had AD at different disease stages would be enlightening.

    The protection against lysosomal defects shown by blocking increased RyR2 Ca2+ release in Mustaly-Kalimi et al. is interesting, as is the close coupling between increased RyR2-induced Ca2+ release and lysosomal alkalinization. This latter finding supports previous work showing PS-1 deletion/FAD causing PS-1 mutants deacidify lysosomes, and increase lysosomal Ca2+ release via TRPML1 endolysosomal Ca2+ channels (Lee et al., 1999).

    In contrast, our recent work discovered that TRMPL1-induced Ca2+ release is down-regulated in iPSC-derived human cortical neurons expressing APOE-ε4 compared to other APOE isoforms, is accompanied by increased levels of lysosomal Ca2+, and that this occurs in the absence of lysosomal alkalinization (Somogyi et al., 2023). Together, these highlight differential pathological effects that may occur in the RyR2/EAL system in neurons in sporadic AD, without PS-1 alterations.

    Interestingly, in cardiomyocytes, RyR2 on the sarcoplasmic reticulum (SR) forms stable complexes with TRPML1 in late endosomes and lysosomes (Thakore et al., 2020). This coupling enables spontaneous RyR2-induced “calcium sparks,” and related Ca2+-activation of K+ channels, which modulate vasoconstriction. Remarkably, in the absence of TRPML1 Ca2+ release, RyR2 can no longer induce Ca2+ sparks, leading to RyR2 hyper-activation, hyper-excitation, and cardiac arrythmias (Thakore et al., 2020), It would be exciting to determine if an analogous situation occurs in neurons in sporadic AD.

    Links between heart and brain health allow the tentative hypothesis that defective RyR2/TRPML1 EAL systems in cardiomyocytes may also occur in dementia/AD. Importantly, we show EAL defects induced by reduced TRPML1 Ca2+ release in neurons can be remediated by small molecule synthetic TRPML1 agonists (Somogyi et al., 2023).

    Both papers focus on Aβ and tau as targets of increased RyR2 activity-induced autophagic failure. However, moving beyond Aβ and tau as autophagic “cargo” should be illuminating. Interestingly, proteomic studies are beginning to identify mitochondria, synaptic, and ER proteins targeted by autophagy to regulate synaptic function and neuronal firing (Coughlan and Maday, 2023), which are likely to be important in AD pathogenesis via the RyR2-EAL system. In summary, these papers have discovered a novel pathway linked to AD pathogenesis and open the door to future discovery to better understand and target increased RyR-2-induced Ca2+ coupling to EAL pathogenesis at early disease stages of AD.   

    References:

    Kelliher M, Fastbom J, Cowburn RF, Bonkale W, Ohm TG, Ravid R, Sorrentino V, O'Neill C. Alterations in the ryanodine receptor calcium release channel correlate with Alzheimer's disease neurofibrillary and beta-amyloid pathologies. Neuroscience. 1999;92(2):499-513. PubMed.

    Somogyi A, Kirkham ED, Lloyd-Evans E, Winston J, Allen ND, Mackrill JJ, Anderson KE, Hawkins PT, Gardiner SE, Waller-Evans H, Sims R, Boland B, O'Neill C. The synthetic TRPML1 agonist ML-SA1 rescues Alzheimer-related alterations of the endosomal-autophagic-lysosomal system. J Cell Sci. 2023 Mar 15;136(6) Epub 2023 Mar 21 PubMed.

    Thakore P, Pritchard HA, Griffin CS, Yamasaki E, Drumm BT, Lane C, Sanders KM, Feng Earley Y, Earley S. TRPML1 channels initiate Ca2+ sparks in vascular smooth muscle cells. Sci Signal. 2020 Jun 23;13(637) PubMed.

    Coughlan ML, Maday S. Beyond housekeeping: autophagy regulates PKA signaling at synapses. Trends Neurosci. 2023 Mar;46(3):167-169. Epub 2023 Jan 28 PubMed.

    View all comments by Cora O'Neill

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