ORCID

https://orcid.org/0000-0002-7229-7136

Department

Biological Sciences

Year of Study

3

Full-time or Part-time Study

Full-time

Level

Postgraduate

Presentation Type

Oral Presentation

Supervisor

Dr Caitriona Guinane

Supervisor

Prof Gerard O’Keeffe

Supervisor

Dr Louise Collins

Abstract

Background

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron degeneration. This degeneration is partly driven by over expression of α-synuclein (α-syn) and development of α-syn aggregates known as Lewy bodies throughout the substantia nigra. As well as motor dysfunction, PD presents with several chronic gastrointestinal comorbidities, which cause a decline of gut microbial diversity and microbially derived short chain fatty acids (SCFAs). Recent in vivo studies have shown SCFAs to be neuroprotective in various degenerative disease states, suggesting that SCFAs may protect against dopaminergic degeneration.

Methods

Human neuroblastoma SH-SY5Y cells were used as a model of human dopaminergic neurons to examine the effects of SCFAs on neurite growth as a single cell readout of neuroprotective efficacy, in the presence and absence of the dopaminergic neurotoxin, 6-hydroxydopamine (6-OHDA) as an in vitro model of PD. Furthermore, we examined the effects of a SCFA combination treatment in SH-SY5Y cells transfected to overexpress wild type a-syn (WT α-syn) as a secondary model of PD related degeneration.

Results

Concurrent sodium acetate (NaOAc) treatment (25 µM – 200 uM) for 72 h, promoted neurite outgrowth in a concentration dependent manner. However, treatment with 50 μM NaOAc did not protect against neurite retraction induced by 10 μM 6-OHDA treatment for 72 h. Conversely, a SCFA combination of 50 μM NaOAc, 50 μM Sodium Butyrate and 50 µM Sodium Propionate did protect against 6-OHDA-induced decreases in neurite growth at 72 h. Similarly, the transfected model of SH-SY5Y cells showed that this concurrent SCFA combination treatment at 50 μM protected against WT α-syn associated neurite retraction at the 72 h timepoint.

Conclusions

These findings provide proof-of-principle that SCFAs may protect against degeneration induced by a neurotoxin and a-syn overexpression in the SH-SY5Y cell line in vitro. This rationalizes the further study of SCFAs and SCFA producing microbes as potential neuroprotective therapies for PD.

Keywords:

Short chain fatty acids(SCFAs), 6-OHDA, SHSY5Y cells, neurite length, Wild type alpha synuclein

Start Date

2-11-2023 12:00 PM

End Date

2-11-2023 12:15 PM

Share

COinS
 
Nov 2nd, 12:00 PM Nov 2nd, 12:15 PM

Short chain fatty acid combination treatment protects against 6-OHDA and WT α-synuclein induced decreases in neurite growth in in vitro models of Parkinson’s disease.

Background

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron degeneration. This degeneration is partly driven by over expression of α-synuclein (α-syn) and development of α-syn aggregates known as Lewy bodies throughout the substantia nigra. As well as motor dysfunction, PD presents with several chronic gastrointestinal comorbidities, which cause a decline of gut microbial diversity and microbially derived short chain fatty acids (SCFAs). Recent in vivo studies have shown SCFAs to be neuroprotective in various degenerative disease states, suggesting that SCFAs may protect against dopaminergic degeneration.

Methods

Human neuroblastoma SH-SY5Y cells were used as a model of human dopaminergic neurons to examine the effects of SCFAs on neurite growth as a single cell readout of neuroprotective efficacy, in the presence and absence of the dopaminergic neurotoxin, 6-hydroxydopamine (6-OHDA) as an in vitro model of PD. Furthermore, we examined the effects of a SCFA combination treatment in SH-SY5Y cells transfected to overexpress wild type a-syn (WT α-syn) as a secondary model of PD related degeneration.

Results

Concurrent sodium acetate (NaOAc) treatment (25 µM – 200 uM) for 72 h, promoted neurite outgrowth in a concentration dependent manner. However, treatment with 50 μM NaOAc did not protect against neurite retraction induced by 10 μM 6-OHDA treatment for 72 h. Conversely, a SCFA combination of 50 μM NaOAc, 50 μM Sodium Butyrate and 50 µM Sodium Propionate did protect against 6-OHDA-induced decreases in neurite growth at 72 h. Similarly, the transfected model of SH-SY5Y cells showed that this concurrent SCFA combination treatment at 50 μM protected against WT α-syn associated neurite retraction at the 72 h timepoint.

Conclusions

These findings provide proof-of-principle that SCFAs may protect against degeneration induced by a neurotoxin and a-syn overexpression in the SH-SY5Y cell line in vitro. This rationalizes the further study of SCFAs and SCFA producing microbes as potential neuroprotective therapies for PD.