Optogenetics: A Light on Neurodegenerative Disorder Alzheimer’s
Talari Hanny Sundara Agnes
M.Sc biotechnology
Pondicherry University
INTRODUCTION
Alzheimer’s is a neurodegenerative disease characterized by neurofibrillary tangles and amyloid plaques, which further lead to cell death and dementia. It accounts for over 60-70% of dementia cases.
There is no proper cure for Alzheimer’s. Currently, deep brain stimulations and pharmacological therapies are used to treat neurological disorders but they lack any of the two qualities, temporal control of neuron and spatial specificity Optogenetics sheds light on the retrieval of memory in Alzheimer’s patient as it can be used to control neurons and it is also spatial specific.
Optogenetics is a technique which uses a combination of optics (light) and genetic engineering to cause changes in neuronal activities and there by regulate neuronal signaling.
THE TOOLS USED IN OPTOGENETICS
i. Optogenetic Actuators: these are the proteins (opsins), when stimulated by light source they alter the activity of the cell in which they are expressed. Mostly microbial opsins like channel rhodopsin, halo rhodopsin, and archaerhodopsin are used as optogenetic actuators.
The channel rhodopsins (chR1 and chR2) are isolated from algae Chlamydomonas reinhardtii, these are cation selective and blue light sensitive, causes depolarization of neuron and stimulates action potential.
Halorhodopsin (NpHR) is isolated from Natronomonas pharanois it is anion sensitive (chloride pump) and sensitive to yellow light, cause hyperpolarization of neuron and inhibits the activity of neuron.
Nowadays, many genetically modified optogenetics actuators are in use.
ii. Light source: LED lasers are targeted at, to sensitize opsins via optic fibers, but using optic fibers cause difficulties in moving mammals. So, nowadays wireless silicon based neural implants etc. are in use.
iii. Vectors: viral vectors like Adeno-associated viral vectors (AVV), Lentiviral vectors are used to transfer opsin into specific neuron.
iii. Optogenetic sensors: optogenetic sensors like
GCaMPs—Calcium sensors,
Synopto-PHliuorin – Vesicular release,
Quasars, ASAPs—Membrane voltage,
GluSnFRs—Neurotransmitters
Helps in controlling and recording neuronal activity.
MECHANISM OF OPTOGENETICS
The opsin genes are integrated into the viral vector having promoter specific to the neuron to be treated and is genetically engineered into the neuronal cells. The opsin genes release photosensitive channel rhodopsin proteins. When a light source is allowed to fall on the cells, these proteins cause changes in ion channels there by stimulating or inhibiting neuronal activity.
APPLICATION OF OPTOGENETICS IN ALZHEIMER’S DISEASE
The hippocampus of brain has two major subtypes of interneurons, parvalbumin-positive (PV) and somatostatin-positive (SST). They are involved in the generation of brain oscillations that include theta (4-12Hz), slow gamma (30-60Hz) and fast gamma (60-120Hz) oscillations. The gamma oscillations are proposed to have functionally distinct role in memory. The impaired gamma oscillations result in Alzheimer’s disease. One of the reasons for the impairment is excessive production and accumulation of the amyloid AβO1-42 peptide, thereby causing the dysfunction of PV and SST interneurons.
The selective optogenetic modulations of these neurons restored the normal oscillations, induced long-term potentiation (LTP), reduced amyloid plague and helped in retrieval of memory in mouse models. Park and his co-workers carried an experiment in mouse model where they injected hippocampal cells with AVV vectors carrying chR2 and C1V1 (AAV-DIO-C1V1-YFP). Then allowed a specific optical stimulation (green light of 565nm), it restored the AβO1-42 induced impairment of theta-nested gamma oscillation. Similarly, when hippocampal cells are modified with specific optogenetic actuators and stimulated with a blue light of 470nm, it fully restored NMDA receptor—dependent tLTP.
Not only in the treatment of Alzheimer’s disease, Optogenetics also explained
· Normal neural circuits and their dysfunctions
· Revealed the memory process
· Modulated neurotransmitter signals
Other than Alzheimer’s, the effect of optogenetics on many neurological disorders, peripheral nervous system disorders are still under study. In February 2015, RetroSense Therpeutics company received an FDA approval for human trails to treat (optogenetics-based therapy) blindness due to retinitis pigmentosa (RP) and advanced dry age-related macular degeneration.
| Neurodegenerative disease | Optogenetic actuators | Promoters | Parameter studied |
| Alzheimer’s disease | Stabilized step-function opsins | CaMKIIα promoter | Amyloid β peptide release |
| Stroke | Channelrhodopsin-2 | Thy1 promoter | Functional recovery |
| Epilepsy | Halo rhodopsin | CaMKIIα promoter | Seizure suppression |
| Parkinson’s disease | Halo rhodopsin | human synapsin promoter | Graft function and graft host connectivity |
| Huntington’s disease | Channelrhodopsin-2 | GABA synaptic D1 or D2 promoters | Sources of increased inhibition |
| Auditory dysfunction | Channelrhodopsin-2, chronos | Cochlear excitation | |
| Retinopathies | Channelrhodopsin-2 | vision |
CONCLUSION
There is still a lot of research going on optogenetics. Further research advancements are required to overcome any disadvantages present in this technique. Also taking ethical issues into consideration optogenetics will be a promising diagnostic and therapeutic tool for neurodegenerative disorders.
Reference (Feb-21-A3)
