The Gregory Lab

Pathobiology & Precision-Prevention in ALS/MND & Other Neurodegenerative Diseases

The Gregory Lab’s (PI Prof. Jenna Gregory) research focuses on pathmechanisms & precision-prevention approaches in neurodegenerative diseases with a focus on ALS/MND. We are based at the Institute of Medical Sciences at the University of Aberdeen, Scotland. Our research interests centre on using histopathological, genetic, transcriptomic, proteomic, clinical & data analytical approaches to probe differences between individuals with ALS/MND. Our aim is to identify therapeutic targets and develop biomarkers for clinical trials.

ALS/MND is a devastating neurogenerative disease with no cure and poor translation from preclinical models to clinical trials – the same is true of many neurodegenerative diseases.

Data suggest that early treatment leads to improved clinical outcomes – but what if we could be diagnosing disease years ahead of symptom onset through precision-prevention approaches.

Priorities:

• Identifying who is at risk, when to intervene and how.
• Take opportunities for early intervention and precision prevention for all, across life course, and prior to end-stage central nervous system disorders.
• Instigate a transformative shift in the diagnostic and therapeutic focus from precision medicine aimed at end-stage, symptomatic individuals to precision-prevention aimed at all, across life course.

Core concepts for our perspective on precision-prevention in ALS/MND:

💭 Perspectives > How can we learn from cancer, where early detection methods have revolutionised outcomes.

💭 Detection > Early detection of ALS/MND years before motor symptoms arise.

💭 Precision > Understanding individual’s risk factors, resilience factors & heterogenous disease manifestations is key.

💭 Prevention > Through safe interventions e.g. lifestyle changes, and/or early triaging to clinical trials for best outcomes.

For cancer, patients are often diagnosed in the GP surgery or by screening programs – for ALS/MND however, all diagnoses are in the outpatient setting when it might be too late to intervene. Through peecision-prevention approaches we can armour our GPs and community diagnostic teams to pick up disease early through advances in biomarker development, recognising  early non-motor disease manifestations, and understanding how peripheral tissues showing pathology years before motor symptom development could provide means of early detection through screening programs.

In this recorded talk (see below) from March 5th, 2025 at LifeArc’s Translational Science Summit on MND & Rare Dementias, Jenna shares a compelling vision for early diagnosis and prevention of MND, emphasizing how we can draw valuable lessons from cancer, where early detection and diagnosis have significantly improved patient outcomes. In this talk, Jenna relates findings from her research group that pathological aggregates of TDP-43 are accumulating years prior to disease onset, identification of which could facilitate early intervention. To address this, she highlights the development of sensitive and specific tools to detect TDP-43 pathology, early, and with minimally invasive point-of-care assays.

If you’re interested in our work on pathobiology and precision-prevention in ALS/MND please see below:

For Prof. Gregory’s work on early detection, and clinical markers, of ALS/MND see:

For Prof. Gregory’s work on non-motor symptoms and extra-motor brain region pathology in ALS/MND see:

Pattle SB, O’Shaughnessy J, Kantelberg O, Rifai OM, Pate J, Nellany K, Hays N, Arends MJ, Horrocks MH, Waldron FM, Gregory JM. pTDP-43 aggregates accumulate in non-central nervous system tissues prior to symptom onset in amyotrophic lateral sclerosis: a case series linking archival surgical biopsies with clinical phenotypic data. Journal of Pathology: Clinical Research 2023; 9: 44-55 [see here for associated preprint].

Gregory JM, Elliott E, McDade K, Bak T, Pal S, Chandran S, Abrahams S, Smith C. Neuronal clusterin expression is associated with cognitive protection in amyotrophic lateral sclerosis. Neuropathology and Applied Neurobiology 2020; 46(3):255-263.

For Prof. Gregory’s work on biomarkers for early pathology detection see:

Spence H*, Waldron FM*, Saleeb RS, Brown AL, Rifai OM, Gilodi M, Read F, Roberts K, Milne G, Wilkinson D, O’Shaughnessy J, Pastore A, Fratta P, Shneider N, Tartaglia GG, Zacco E, Horrocks MH, Gregory JM. RNA aptamer reveals nuclear TDP-43 pathology is an early aggregation event that coincides with STMN-2 cryptic splicing and precedes clinical manifestation in ALS. Acta Neuropathologica 2024; Mar 5;147(1):50 [See here for associated preprint, and here for associated laboratory SOP for TDP-43 RNA aptamer staining in FFPE human tissue]. *equal contributions.

Mehta AR, Selvaraj BT, Barton SK, McDade K, Abrahams S, Chandran S, Smith C, Gregory JM. Improved detection of RNA foci in C9orf72 amyotrophic lateral sclerosis post-mortem tissue using BaseScope™ shows a lack of association with cognitive dysfunction. Brain Communications 2020; 2(1):fcaa009.

Zacco E, Kantelberg O, Milanetti E, Armaos A, Panei FP, Gregory JM, Jeacock K, Chandran S, Clarke D, Ruocco G, Gustincich S, Horrocks M, Pastore A, Tartaglia GG. Probing TDP-43 condensation using an in silico designed aptamer. Nature Communications 2022; 13: 3306.

For Prof. Gregory’s work on how AI and machine learning can power accurate ALS diagnosis and cognitive impairment detection see:

Xia Y, Gregory JM, Waldron FM, Spence H, Vallejo M. Integrating transfer learning and attention mechanisms for accurate ALS diagnosis and cognitive impairment detection. medRxiv 2024 DOI: 10.1101/2024.09.22.24313406.

Rifai OM, Longden J, O’Shaughnessy J, Sewell MDE, Pate J, McDade K, Daniels MJD, Abrahams S, Chandran S, McColl BW, Sibley CR, Gregory JM.  Random forest modelling demonstrates microglial and protein misfolding features to be key phenotypic markers in C9orf72-ALS. Journal of Pathology 2022; Dec;258(4):366-381 [see here for associated preprint].

For Prof. Gregory’s work on disease heterogeneity in ALS/MND see:

Rifai OM, O’Shaughnessy J, Dando OR, Munro AF, Sewell MDE, Abrahams S, Waldron FM, Sibley CR, Gregory JM. Distinct neuroinflammatory signatures exist across genetic and sporadic amyotrophic lateral sclerosis cohorts. Brain 2023; 146(12):5124-5138 [See here for associated preprint].

For Prof. Gregory’s work on therapeutic targets for ALS/MND see:

Banerjee P, Elliott E, Rifai OM, O’Shaughnessy J, McDade K, Abrahams S, Chandran S, Smith C, Gregory JM. NLRP3 inflammasome as a key molecular target underlying cognitive resilience in amyotrophic lateral sclerosis. Journal of Pathology 2022; 256(3):262-268. [click here for associated Invited Commentary; Mehta, P.R., Lashley, T., Fratta, P. and Bampton, A. Markers of cognitive resilience and a framework for investigating clinical heterogeneity in ALS. Journal of Pathology 2022; 257: 251-254].

Elliott E, Bailey O, Waldron FM, Hardingham GE, Chandran S, Gregory JM. Therapeutic targeting of proteostasis in amyotrophic lateral sclerosis – a systematic review and meta-analysis of preclinical research. Frontiers in Neuroscience 2020; 14:511.