The Inborn Errors of Metabolism (IEM) have normally been considered as the result of errors at the genetic level affecting the biochemical pathways of small molecules such as the neurotransmitters glycine, glutamate, GABA, biogenic amines, etc. The altered concentration of such molecules in the Cerebrospinal Fluid (CSF) have always been used as a diagnostic biomarker of IEM of neurotransmitters.

However, the most recent findings in the neuroscience field have been changing and increasing the range of the classic definition of IEM. The synthesis, transport, and catabolism of neurotransmitters are not seen anymore as the only mechanisms that regulate neurotransmission. For example, the synaptic vesicles (SVs), which transport the neurotransmitters, participate in many biochemical pathways, from their budding in the Endoplasmic Reticulum (ER), through their transport along the neuronal body, to their fusion at the presynaptic plasma membrane that permits the exocytosis of the neurotransmitters. Different biochemical pathways take part on this journey, for example, many of them regard the metabolism of fatty acids. So, the concept of IEM is broadening, adding new pathways and new genes as possible causes of neurological diseases.

Not only neurotransmitters: how the journey of the SVs influences the neurotransmission

From the point of view of the cellular biology, the synaptic transmission in neurons can be described in three main phases.

1) The vesicle synthesis in the neuronal body. The synthesis of the SVs starts in the membranes of the ER and continues through the Golgi membranes. During this phase, a lot of signalization proteins are involved. They have two main functions: they define which kind of molecules will be loaded in the newborn vesicles and decide their final destination, for example, the SV can reach the plasma membrane or can go to recycling endosomes. These signalization proteins are called Coat Proteins.

Not only proteins but also different lipids participate in the synthesis of the SVs. Their type and composition vary depending on the specific cell and on the molecules to be transported. The SVs ready to leave the ER and the Golgi apparatus can be divided into two categories according to on their size:

– the large dense core vesicles (LDCVs) have a size ranging from 75 to 95 nm and transport neuropeptides and proteins to be released into the extracellular space;

– the small vesicles (40 to 50 nm) store and deliver small neurotransmitters such as monoamines, GABA, glycine, glutamate, acetylcholine and serine.

2) The axonal transport. The SVs can move through the neuron axonal body at different speeds. In the fast transport system, mainly used for vesicles, organelles and RNA, they reach 50-200 mm/day. The slow transport system reaches the speed of 0.1-3 mm/day: cytoskeletal components and some proteins move in this manner.

The motor proteins permitting the transport through the whole axon are the kinesins and the dyneins. The kinesins are responsible for the so-called anterograde transport (from the center to the periphery of the neurons), while the dyneins move the cargoes from the axon tips to the cell body with a retrograde transport.

More information about the transport mechanisms can be found in an article previously published on this blog:

3) The SVs exocytosis and the release of the neurotransmitters. Once they have reached the presynaptic compartment, the SVs are filled with the appropriate neurotransmitter through specific transporters. Both SVs and LDCVs release their content through exocytosis mechanisms regulated by calcium, even if in different sites and with different releasing mechanisms. The exocytosis is also regulated by many types of proteins, such as the proteins of the SNARE complex, but their role has not been fully understood yet.

The importance of lipids

In the last five years, more than one hundred of diseases have been related to defects of the lipid metabolism. Lipids have a key role in the synaptic communications that reflects in the nervous system disorders when their biochemical pathways do not work well. Among the lipids involved in the biology of the SVs:

– polyphosphoinositides and phosphatidylcholine play a role in neurotransmission by regulating the exo- and endocytosis of the SVs;

– diacylglycerol and phosphatidic acid are needed for exocytosis, as well as sphingosine;

– cone-shaped lipids are involved in the membrane fusion and in the geometry of the vesicles.

In general, there is a close cooperation between the lipids and the proteins involved in these processes: the neurotransmission is only possible if both work in tandem.

From cell biology to genetic: the diseases of the SVs

Many genes of the protein and lipid metabolism are involved in each of the three steps described before. Just focusing on monogenic disorders, a lot of diseases can arise.

Defects in genes codifying for proteins and lipids in the vesicle synthesis at the level of the ER or of the Golgi: the malfunction of the enzymes responsible for the glycosylation leads to errors in vesicles synthesis. The diseases associated vary from intellectual disability to hypotonia, epilepsy, and ataxia.

When genes involved in the axonal transport are affected, diseases as hereditary spastic paraparesis (HSP) arise. Mutations of kinesins produce, among others, axial hypotonia and cerebellar atrophy. The malfunction of the kinase p38 MAPK is related to the amyotrophic lateral sclerosis (ALS).

At the presynaptic level, if the SNARE complex does not work properly, epilepsy, movement disorders and autism spectrum disorder appear.

Conclusions. The importance of finding reliable biomarkers

The recent findings outlined here open new possibilities in the understanding of the molecular basis of many neurological diseases, but at the same time make difficult to reach a diagnosis. Many of the biomarkers are only available in the CSF: this means the need of invasive test to extract CSF samples from the patients – that is not always possible – and the need to rely on few, highly specialized centers. Moreover, in some cases, there are normal levels of biomarkers even in the presence of a disease.

For these reasons, it will be important to find new reliable biomarkers by developing new tests and by improving the knowledge in many -omics fields, such us metabolomics, proteomics, and others.



Cortés-Saladelafont E. et al. Diseases of the synaptic vesicle: a potential new group of neurometabolic disorders affecting neurotransmission. Semin Pediatr Neurol. 2016 Nov;23(4):306-320



The elaboration of this post has been financed by the project PI15/01082, as a part of the National Plan of I+D+I and co-financed by the ISCIII – General Deputy Direction for Evaluation and Development of Health Research – and the European Regional Development Fund (ERDF).