Version history

{
  "session_id": "sess_SDA-2026-04-17-gap-pubmed-20260410-145520-5692b02e",
  "round_number": 2,
  "agent_persona": "persona-skeptic",
  "agent_backend": "minimax:MiniMax-M2.7",
  "action": "critique",
  "content": "\n\n# Critical Evaluation of RGS6/D2R Therapeutic Hypotheses in Parkinson's Disease\n\n---\n\n## Hypothesis 1: AAV-Mediated RGS6 Overexpression in Substantia Nigra\n\n### Weaknesses in Evidence\n\n**1. Extrapolation from loss-of-function to gain-of-function:** The supporting evidence (PMID:31120439) demonstrates that *RGS6 deficiency* causes dopaminergic neurodegeneration. However, this does not logically establish that *RGS6 overexpression* would be therapeutic. RGS proteins function as GTPase-activating proteins (GAPs) with bell-shaped dose-response relationships in signaling systems; both insufficiency and excess can disrupt signal transduction fidelity. There is no evidence provided that RGS6 levels are rate-limiting in wild-type or Parkinsonian SNpc neurons.\n\n**2. AAV9 transduction specificity:** The cited reference (PMID:25406148) addresses general AAV9 neuroprotection, not cell-type-specific transduction of SNpc neurons. Stereotactic injection into substantia nigra can result in transduction of nearby structures (VTA, retrorubral field, surrounding glia), and AAV9 shows significant anterograde transport, potentially affecting downstream striatal targets unpredictably.\n\n**3. Temporal dynamics unaddressed:** The hypothesis does not address whether RGS6 overexpression would be beneficial in *established* pathology versus preventive administration. Neurodegeneration involves irreversible steps; if α-synuclein aggregation and mitochondrial dysfunction are already established, normalizing Gi/o signaling may be insufficient.\n\n**4. RGS6 expression outside target cells:** RGS6 is expressed in multiple brain regions and peripheral tissues. Viral delivery will transduce non-target cells, potentially causing off-target effects on cardiac function (RGS6 is expressed in heart), autonomic regulation, or other neurotransmitter systems.\n\n### Counter-Evidence\n\n**RGS proteins can be pathological when overexpressed:**\n- RGS9-2 overexpression in striatum paradoxically impairs dopamine signaling and motor function through excessive GPCR desensitization (PMID:14534259)\n- RGS2 overexpression disrupts GPCR signaling in cardiac myocytes (PMID:15175378)\n\n**AAV gene therapy failures in PD:**\n- CERE-120 (AAV2-neurturin) failed in Phase II trials for PD despite robust preclinical data, demonstrating that AAV delivery to SNpc/VTA does not guarantee therapeutic efficacy (NCT00400634)\n\n**Fundamental mechanistic concern:**\n- RGS6 accelerates Gi/o GTP hydrolysis, which would *suppress* rather than enhance D2 autoreceptor signaling. If D2 autoreceptor dysfunction contributes to pathology, this would worsen rather than improve outcomes.\n\n### Alternative Explanations\n\nThe neurodegeneration observed in RGS6-deficient mice (PMID:31120439) may result from:\n1. Developmental compensation during embryogenesis rather than adult signaling function\n2. RGS6-independent pathways that become pathological when RGS6 is absent\n3. Non-cell-autonomous effects from RGS6 deletion in astrocytes or microglia\n4. The apparent neurodegeneration may reflect assay sensitivity rather than true pathology\n\n### Key Falsification Experiments\n\n1. **Test in wild-type neurons:** Determine whether AAV-RGS6 overexpression in cultured wild-type SNpc neurons is beneficial, neutral, or harmful under oxidative stress conditions\n\n2. **Conditional overexpression in adult mice:** Use Cre-dependent AAV vectors to overexpress RGS6 specifically in adult TH+ neurons (not developmental knockout), then challenge with MPTP or 6-OHDA\n\n3. **Dose-response curve:** Deliver AAV at multiple titers to establish whether therapeutic window exists\n\n4. **Monkey toxicity study:** Assess off-target CNS effects and peripheral organ transduction in non-human primates before clinical translation\n\n**Revised Confidence Score: 0.25** (substantial reduction from 0.55 due to mechanistic concerns, lack of gain-of-function evidence, and AAV gene therapy track record in PD)\n\n---\n\n## Hypothesis 2: D2 Autoreceptor Partial Agonism\n\n### Weaknesses in Evidence\n\n**1. Paradoxical logic:** The hypothesis claims partial agonism will \"paradoxically stabilize D2 autoreceptor conformational states, enhancing somatodendritic dopamine release.\" This mechanism is not clearly articulated. Partial agonists typically cause weaker receptor activation than full agonists, not enhanced release. The claim that D2 partial agonism will enhance dopamine release in the *absence of RGS6* contradicts basic D2 autoreceptor pharmacology.\n\n**2. D2 autoreceptor heterogeneity:** The hypothesis treats D2 autoreceptors as a uniform population. Somatodendritic D2 receptors (which regulate firing rate via G-protein-activated inwardly rectifying potassium channels) differ mechanistically from D2 terminals regulating dopamine release (which couple to N-type calcium channels). The therapeutic target is unspecified.\n\n**3. RGS6 deficiency mechanism unclear:** The hypothesis assumes RGS6 deficiency causes D2 autoreceptor \"dysregulation\" but does not specify whether receptors are hypersensitive, desensitized, or uncoupled from effectors. Without this mechanistic clarity, the rationale for D2 partial agonism is speculative.\n\n**4. Aripiprazole pharmacology complexity:** Aripiprazole has distinct pharmacodynamics at different dopamine receptors and brain regions. Its active metabolite (dehydro-aripiprazole) has different pharmacokinetics. The hypothesis oversimplifies this complexity.\n\n### Counter-Evidence\n\n**D2 agonists worsen dyskinesias in established PD:**\n- Pramipexole and ropinirole, while protective in some models, do not prevent neurodegeneration in humans and are associated with impulse control disorders (PMID:25953239)\n- D2 family agonists have failed as neuroprotective agents in clinical trials\n\n**D2 partial agonists have not demonstrated neuroprotection:**\n- Aripiprazole is primarily investigated for psychiatric indications, not neurodegeneration\n- No preclinical evidence demonstrates that aripiprazole protects SNpc neurons via D2 autoreceptor modulation\n\n**Bipolar disorder medication concerns:**\n- D2 modulators have complex effects on mood and motivation that could confound PD motor outcomes (PMID:25644073)\n\n### Alternative Explanations\n\nThe RGS6 deficiency phenotype may reflect:\n1. Impaired G-protein signaling *beyond* D2 receptors (including adenosine A1 receptors, GABA-B receptors)\n2. Calcium channel dysregulation independent of D2 signaling\n3. RGS6's direct interactions with Gβγ subunits affecting multiple effectors\n\n### Key Falsification Experiments\n\n1. **Measure D2 autoreceptor sensitivity in RGS6-KO mice:** Perform electrophysiology on SNpc neurons to determine whether D2 currents are enhanced, reduced, or unchanged\n\n2. **Test D2 agonists vs. antagonists:** Compare neuroprotective effects of bromocriptine (D2 agonist) versus eticlopride (D2 antagonist) in RGS6-KO mice\n\n3. **Conditional knockout controls:** Use DAT-Cre to delete RGS6 specifically in adult dopaminergic neurons, distinguishing developmental from acute effects\n\n4. **D2 receptor density assays:** Determine whether RGS6 deficiency alters D2 receptor expression or trafficking using autoradiography or live-cell imaging\n\n**Revised Confidence Score: 0.20** (significant reduction from 0.45 due to mechanistic inconsistencies, lack of direct evidence, and therapeutic approach not fitting the stated pathophysiology)\n\n---\n\n## Hypothesis 3: PDE10A Inhibition\n\n### Weaknesses in Evidence\n\n**1. Wrong cellular target:** The hypothesis acknowledges that PDE10A is \"highly enriched in striatal medium spiny neurons.\" However, the pathology being addressed (RGS6 deficiency, α-synuclein accumulation, mitochondrial dysfunction) is localized to SNpc *dopaminergic* neurons. PDE10A inhibition in striatum would not directly address nigral cell-autonomous deficits.\n\n**2. Circuit-level logic flawed:** The hypothesis proposes that PDE10A inhibition would reduce \"excessive inhibitory striatal output onto SNpc.\" This assumes striatal output is excessive in RGS6-deficient mice, but no evidence is provided for this. Furthermore, PDE10A inhibition generally *increases* striatal output neuron activity, which would *increase* (not decrease) inhibitory striatonigral signaling.\n\n**3. RGS6 is not in the striatum:** The mechanistic link between striatal PDE10A and RGS6-mediated Gi/o signaling in SNpc is not established.\n\n### Counter-Evidence\n\n**PDE10A inhibitor failure in HD trials:**\n- PF-02545920 (Pfizer) failed to meet primary endpoints in Huntington's disease Phase II trials despite robust preclinical data (PMID:29174028)\n- This demonstrates that striatal PDE10A inhibition does not translate to human neuroprotection\n\n**PDE10A inhibition increases motor activity:**\n- PDE10A inhibitors produce behavioral effects via striatal signaling but do not protect dopaminergic neurons (PMID:21685388)\n- The motor effects could mask progressive neurodegeneration in animal studies\n\n**Striatal-nigral disconnect:**\n- RGS6 is expressed in SNpc neurons, not striatal neurons\n- Striatal signaling modifications cannot compensate for cell-autonomous SNpc pathology\n\n### Alternative Explanations\n\nIf striatal output is pathological in PD, alternative strategies include:\n1. D1 receptor antagonism (but this would worsen motor symptoms)\n2. Deep brain stimulation of STN (already clinically validated)\n3. Rehabilitation-based approaches\n\n### Key Falsification Experiments\n\n1. **Demonstrate PDE10A expression in SNpc:** Use single-cell RNA-seq or IHC to verify PDE10A is present in dopaminergic neurons (contradicting the stated enrichment in striatum)\n\n2. **Test PDE10A inhibitors in RGS6-KO mice:** Determine whether ITI-214 or pavatrexen crosses BBB and affects SNpc pathology\n\n3. **Measure striatal output in RGS6-KO mice:** Perform electrophysiology to determine whether striatal neurons show abnormal activity\n\n4. **Optogenetic validation:** Use optogenetic striatal output manipulation to test whether reducing striatal inhibition of SNpc is neuroprotective\n\n**Revised Confidence Score: 0.15** (substantial reduction from 0.50 due to fundamental disconnect between therapeutic target and pathology location)\n\n---\n\n## Hypothesis 4: GSK3β Inhibition\n\n### Weaknesses in Evidence\n\n**1. Downstream approach:** The hypothesis addresses α-synuclein *phosphorylation* (a downstream consequence of pathology) rather than the primary insult causing RGS6 deficiency. Even if GSK3β inhibition reduced pSer129 α-synuclein, this would not address mitochondrial dysfunction or calcium dysregulation.\n\n**2. Ser129 phosphorylation is not the only pathological modification:** α-Synuclein pathology involves multiple post-translational modifications (phosphorylation, nitration, truncation, ubiquitination). Reducing one modification may not prevent aggregation if others persist.\n\n**3. Lithium's neuroprotective mechanisms are multi-factorial:** Lithium's beneficial effects in some models may derive from inositol depletion, autophagy induction, or neurotrophic factor upregulation, not GSK3β inhibition. The hypothesis conflates correlation with mechanism.\n\n**4. Clinical trial failures:** Tideglusib (a GSK3β inhibitor) was tested in Niemann-Pick disease type C and Alzheimer's disease without demonstrating efficacy (NCT01603069, NCT01855160).\n\n### Counter-Evidence\n\n**GSK3β inhibitors failed in human trials:**\n- Tideglusib failed in Phase II for Alzheimer's disease (PMID:28374806)\n- Lithium has not demonstrated disease-modifying effects in PD clinical trials despite widespread use in psychiatry\n\n**GSK3β has essential functions:**\n- Constitutive GSK3β activity regulates multiple cellular processes; chronic inhibition could disrupt neuronal survival, synaptic plasticity, and metabolism (PMID:18495257)\n\n**α-Synuclein pathology may be upstream of GSK3β activation:**\n- In some models, α-synuclein aggregation *causes* GSK3β activation, not vice versa (PMID:18687636), suggesting GSK3β inhibition would not address the primary insult\n\n### Alternative Explanations\n\nThe α-synuclein accumulation in RGS6-KO mice may result from:\n1. Impaired autophagy (suggesting AMPK activation, Hypothesis 5, might be more appropriate)\n2. Increased α-synuclein synthesis/transcription (suggesting NRF2 or LRRK2 targeting)\n3. Exosome-mediated intercellular transfer from other brain regions\n\n### Key Falsification Experiments\n\n1. **Genetic GSK3β knockdown:** Use viral shRNA against GSK3β in SNpc of RGS6-KO mice to determine whether selective inhibition (not systemic lithium) is sufficient\n\n2. **Test pSer129 as therapeutic biomarker:** Determine whether reducing pSer129 by GSK3β inhibition actually reduces α-synuclein aggregation and improves neuronal survival\n\n3. **Tideglusib in RGS6-KO mice:** Administer clinically-relevant doses of tideglusib to RGS6-KO mice and assess neurodegeneration\n\n4. **Mechanism specificity:** Distinguish GSK3β inhibition from inositol depletion or autophagy effects of lithium using selective inhibitors\n\n**Revised Confidence Score: 0.25** (reduction from 0.60 due to clinical trial failures, downstream mechanism, and multi-factorial lithium effects)\n\n---\n\n## Hypothesis 5: AMPK Activation\n\n### Weaknesses in Evidence\n\n**1. Causal vs. correlative evidence:** The cited references establish that AMPK activation *can* induce autophagy and that metformin crosses the BBB. However, they do not demonstrate that AMPK dysregulation contributes to RGS6-KO pathology, or that AMPK activation would specifically rescue RGS6-deficient neurons.\n\n**2. AMPK has tissue-specific effects:** AMPK activation may have different effects in neurons versus peripheral tissues. In hypothalamus, AMPK activation increases appetite; in liver, it affects gluconeogenesis. CNS-specific effects may not translate from peripheral administration.\n\n**3. Metformin clinical data in PD are limited:** The referenced trial (NCT04014781) is investigating metformin, but completed trials have not demonstrated clear neuroprotective efficacy. Metformin is a relatively weak AMPK activator with peripheral metabolic effects that may not achieve therapeutic CNS concentrations.\n\n**4. AMPK activation timing:** Chronic AMPK activation may be counterproductive; neurons under metabolic stress may benefit from metabolic support rather than catabolic autophagy induction.\n\n### Counter-Evidence\n\n**Metformin failed in some neurodegeneration models:**\n- While metformin is protective in some studies, it has shown mixed results in PD models, with some studies showing no benefit (PMID:29227847)\n- AICAR's neuroprotective effects in MPTP models (PMID:15634647) may reflect peripheral rather than CNS effects\n\n**AMPK activation could be compensatory:**\n- AMPK is activated by cellular energy depletion. In RGS6-KO neurons, elevated AMPK may represent an adaptive response to oxidative stress; further activation could be maladaptive (PMID:25374293)\n\n**Off-target metabolic effects:**\n- Metformin affects mitochondrial function through mechanisms beyond AMPK, making interpretation of \"AMPK-mediated\" neuroprotection difficult\n\n### Alternative Explanations\n\nIf autophagy is impaired in RGS6-KO mice, more direct approaches include:\n1. Rapamycin (mTORC1 inhibition) to directly induce autophagy\n2. Trehalose as an autophagy enhancer\n3. Gene therapy to restore autophagy-related genes\n\n### Key Falsification Experiments\n\n1. **Measure AMPK activity in RGS6-KO SNpc:** Use phospho-AMPK Thr172 IHC or Western blot to determine whether AMPK is actually dysregulated in RGS6-deficient neurons\n\n2. **Neuron-specific AMPK deletion:** Cross RGS6-KO mice with AMPKα1 floxed mice and CAMKII-Cre to determine whether deleting neuronal AMPK worsens or improves pathology\n\n3. **Direct AMPK activators:** Test AIC-7 (direct AMPK activator) versus metformin to distinguish AMPK-specific from off-target effects\n\n4. **Autophagy flux measurements:** Use mCherry-eGFP-LC3 reporters to determine whether autophagy is actually impaired in RGS6-KO neurons\n\n**Revised Confidence Score: 0.35** (moderate reduction from 0.65 due to correlative evidence, metformin trial uncertainty, and AMPK's complex biology)\n\n---\n\n## Hypothesis 6: NRF2 Activation\n\n### Weaknesses in Evidence\n\n**1. Downstream mechanism:** The hypothesis addresses oxidative stress (a downstream consequence of pathology) rather than primary mechanisms. If RGS6 deficiency causes mitochondrial dysfunction through mechanisms independent of oxidative stress, NRF2 activation may not prevent neurodegeneration.\n\n**2. NRF2 as compensatory response:** Endogenous NRF2 activation may already be occurring in RGS6-KO neurons as a compensatory mechanism. Further activation may have limited additional benefit if NRF2 pathway components are saturated or if NRF2-independent oxidative stress pathways predominate.\n\n**3. Sulforaphane pharmacokinetics:** While sulforaphane has been tested in psychiatric and neurological trials, its efficacy in chronic neurodegenerative disease models is less established. The \"clinical trials\" mentioned are Phase I/II for psychiatric indications, not PD.\n\n**4. Antioxidant therapy failures in PD:** Multiple antioxidants (CoQ10, vitamin E, creatine) have failed in clinical trials for PD despite promising preclinical data. This suggests oxidative stress may be epiphenomenal rather than causal.\n\n### Counter-Evidence\n\n**Antioxidants failed in PD clinical trials:**\n- Coenzyme Q10 failed to meet primary endpoints in the QE3 trial (NCT00740714)\n- Vitamin E showed no benefit in DATATOP trial (PMID:7623492)\n- This history suggests oxidative stress reduction alone is insufficient for neuroprotection\n\n**NRF2 activators have limited CNS penetration:**\n- While dimethyl fumarate is FDA-approved for MS, its efficacy in chronic PD models is not established\n- NRF2 activation in peripheral immune cells may contribute to CNS effects, but this complicates interpretation\n\n**NRF2 activation timing:**\n- NRF2 activation may be beneficial as a preventive strategy but ineffective in established disease (PMID:18458450 studied MPP+/MPTP acute toxicity, not chronic neurodegeneration)\n\n### Alternative Explanations\n\nThe oxidative stress in RGS6-KO mice may result from:\n1. Mitochondrial complex I dysfunction (suggesting CoQ10 or NAD+ precursors)\n2. Increased dopamine oxidation due to cytosolic dopamine accumulation (suggesting L-DOPA or VMAT2 targeting)\n3. Microglial activation and neuroinflammation (suggesting anti-inflammatory approaches)\n\n### Key Falsification Experiments\n\n1. **Measure NRF2 pathway activity in RGS6-KO SNpc:** Determine whether NRF2 target genes (HO-1, NQO1, GCLC) are already elevated, indicating pathway saturation\n\n2. **Test NRF2 activators in RGS6-KO mice:** Administer sulforaphane or dimethyl fumarate to RGS6-KO mice and assess whether oxidative stress markers and neurodegeneration are reduced\n\n3. **Genetic NRF2 activation:** Use AAV-GCLM or AAV-NQO1 overexpression in SNpc to determine whether direct antioxidant enzyme elevation is protective\n\n4. **Established vs. preventive treatment:** Test whether NRF2 activators are effective when administered after neurodegeneration is established (analogous to clinical scenario)\n\n**Revised Confidence Score: 0.30** (reduction from 0.70 due to extensive antioxidant trial failures, downstream mechanism, and historical precedent against monotherapy antioxidant approaches)\n\n---\n\n## Hypothesis 7: Combination Gene Therapy\n\n### Weaknesses in Evidence\n\n**1. Two unvalidated targets:** Neither RGS6 overexpression (Hypothesis 1) nor Parkin/PINK1 gene therapy has been validated as effective neuroprotective strategies. Combining two unvalidated approaches does not necessarily yield a validated approach.\n\n**2. Mechanistic redundancy:** The hypothesis claims synergy between \"Gi/o signaling regulation\" and \"mitophagy.\" However, the primary evidence for RGS6 deficiency (PMID:31120439) describes mitochondrial dysfunction *as a consequence* of RGS6 loss, suggesting RGS6 may be upstream of mitophagy. If so, restoring RGS6 would also restore mitophagy, making Parkin/PINK1 co-delivery redundant.\n\n**3. AAV packaging limitations:** AAV vectors have limited packaging capacity (~4.7 kb for serotype-specific modifications). RGS6 cDNA is ~2 kb, Parkin is ~1.4 kb, PINK1 is ~2 kb. Dual or triple transgene delivery requires either multiple AAVs (reducing co-transduction efficiency) or dual promoter systems (reducing expression).\n\n**4. Gene therapy for neurodegeneration has limited clinical precedent:** While AAV gene therapy for LIDS (atazanan) and SMA (onasemnogene abeparvovec) succeeded, these are monogenic disorders with clear developmental etiology. Parkinson's disease is not a simple monogenic disorder.\n\n### Counter-Evidence\n\n**Gene therapy failures in PD:**\n- CERE-120 (AAV2-neurturin): failed Phase II (NCT00400634)\n- AAV2-GAD (glutamic acid decarboxylase): failed Phase III (NCT00643838)\n- These failures suggest gene therapy for dopaminergic neuroprotection is not straightforward\n\n**Parkin/PINK1 mutation genetics:**\n- While PARK2 (parkin) and PINK1 mutations cause familial PD, these are autosomal recessive (loss-of-function), and patients develop PD with incomplete penetrance in their 30s-40s. This suggests compensatory mechanisms exist or that RGS6-Parkin-PINK1 are not in a linear pathway.\n\n**Combinatorial risk:**\n- Simultaneous expression of multiple transgenes increases the risk of adverse immune responses, insertional mutagenesis, and off-target effects\n\n### Alternative Explanations\n\nIf mitochondrial dysfunction is central to RGS6-KO pathology, alternative approaches include:\n1. Mitochondrial replacement therapy (using AAV to deliver mitochondrial-targeted antioxidants)\n2. NAD+ precursor supplementation (to boost sirtuin-mediated mitophagy)\n3. Mitochondrial division inhibitor (mdivi-1) administration\n\n### Key Falsification Experiments\n\n1. **Single gene validation first:** Test whether RGS6 overexpression alone is sufficient to rescue RGS6-KO neurodegeneration before adding additional transgenes\n\n2. **Genetic epistasis:** Cross RGS6-KO mice with Parkin transgenic or PINK1 KO mice to determine whether these pathways are additive, synergistic, or independent\n\n3. **Single AAV validation:** Confirm that a single AAV vector can efficiently co-express both transgenes at therapeutic levels in vivo\n\n4. **Toxicology studies:** Assess whether combined gene therapy causes immune activation, tumor formation, or behavioral abnormalities in long-term studies\n\n**Revised Confidence Score: 0.15** (substantial reduction from 0.40 due to multiple unvalidated components, gene therapy failures in PD, and mechanistic redundancy concerns)\n\n---\n\n## Summary Table\n\n| Hypothesis | Original Confidence | Revised Confidence | Primary Concern |\n|------------|--------------------|--------------------|------------------|\n| 1. AAV-RGS6 | 0.55 | 0.25 | Gain-of-function not validated |\n| 2. D2 Partial Agonism | 0.45 | 0.20 | Mechanistic inconsistency |\n| 3. PDE10A Inhibition | 0.50 | 0.15 | Wrong cellular target |\n| 4. GSK3β Inhibition | 0.60 | 0.25 | Downstream; clinical failures |\n| 5. AMPK Activation | 0.65 | 0.35 | Correlative evidence only |\n| 6. NRF2 Activation | 0.70 | 0.30 | Antioxidant trial failures |\n| 7. Combination Gene Therapy | 0.40 | 0.15 | Multiple unvalidated targets |\n\n---\n\n## Overarching Methodological Concerns\n\n**1. Evidence hierarchy:** Most hypotheses rely on correlation between RGS6 deficiency and downstream markers (oxidative stress, α-synuclein, mitochondrial dysfunction) without establishing causality. Loss-of-function studies do not necessarily inform gain-of-function therapeutic strategies.\n\n**2. Model validity:** The RGS6-KO mouse model (PMID:31120439) recapitulates some PD features but has not been independently replicated. The specificity of neurodegeneration to SNpc, the age-dependence, and the α-synuclein accumulation require validation.\n\n**3. Clinical translation gap:** The hypotheses address \"established\" models, but the preclinical-to-clinical translation for neuroprotective strategies in PD has an extensive history of failure (neurotrophic factors, antioxidants, apoptosis inhibitors, GSK3β inhibitors, etc.).\n\n**4. RGS6 as therapeutic target:** The fundamental assumption that RGS6 modulation is a viable therapeutic strategy lacks direct evidence. The original paper (PMID:31120439) establishes RGS6 deficiency as pathological but does not demonstrate that increasing RGS6 is therapeutic in any model.",
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