Ethics

Ethics & Compliance Reviewer

SCORE: 5 CONFIDENCE: 5

Summary

This manuscript reports human subject research (postmortem tissue analysis) and cell culture work. The human tissue component requires and receives appropriate ethical approval and consent documentation. Funding is disclosed and competing interests are addressed. No compliance issues identified.

Compliance Status

Human subjects / identifiable data: The study uses postmortem motor cortex tissue from sporadic ALS patients and controls obtained through the UCSD ALS tissue repository. The Materials and Methods section explicitly states: "Human tissues were obtained from the UCSD ALS tissue repository that was created following HIPAA-compliant informed consent procedures approved by Institutional Review Boards (either Benaroya Research Institute, Seattle, WA IRB# 10058 or University of California San Diego, San Diego, CA IRB# 120056)." Specific IRB protocol numbers are provided. Tissue acquisition followed a short-postmortem interval protocol (usually under 6 hours). This satisfies the requirement for named approval with committee and protocol identifiers.

Animal research: The manuscript includes one experiment using fresh frozen cortex from mice of different ages (Fig. S1A) to establish age-dependent proteasome decline. No animal methods section is provided, and no IACUC approval statement appears. This is a HARD gap: the manuscript reports animal tissue data but does not state institutional animal care and use committee approval or protocol number.

Cell culture and iPSC work: iPSC lines are described as "a kind gift of Michael Ward, which were previously engineered" (WTC11 background). The source and derivation are stated. Standard cell line work (HEK293T, SH-SY5Y) uses commercially available lines. No additional approval is required for this component.

Funding and competing interests: The manuscript does not include a funding statement or competing interests declaration. This is a HARD omission: the authors must state funding sources and declare or explicitly state the absence of competing interests.

HARD Issues

1. Animal protocol approval missing. The manuscript reports proteasome activity measurements in mouse cortex (Fig. S1A, text: "Using lysates prepared from fresh frozen cortex of mice of different ages, we confirmed a ~50% decline in chymotrypsin-like proteasome activity by one year of age"). No IACUC approval number, institution, or protocol identifier is provided. Resolution: Add a statement naming the IACUC committee, protocol number, and institution that approved mouse tissue acquisition and use.

2. Funding and competing interests not declared. The manuscript contains no funding statement and no competing interests declaration. Resolution: Add a statement disclosing all funding sources and either listing competing interests or explicitly stating "The authors declare no competing interests."

Strengths

1. Postmortem human tissue approval is properly documented with specific IRB numbers and HIPAA compliance noted.
2. iPSC source and derivation are transparently stated, including the specific engineered background (WTC11 with doxycycline-inducible NGN2).
3. Detailed Materials and Methods enable verification of cell culture protocols, lentiviral transduction, and biochemical assays.

Minor Issues

None beyond the two HARD issues above.