Golgi trafficking defects in postnatal microcephaly: The evidence for “Golgipathies”

Abstract

The Golgi apparatus plays a central role in cell homeostasis, not only in processing and maturing newly synthesized proteins and lipids but also in orchestrating their sorting, packing, routing and recycling on the way to their final destination. These multiple secretory pathways require a complex ballet of vesicular and tubular carriers that continuously bud off from donor membranes and fuse to acceptor membranes. Membrane trafficking is particularly prominent in axons, where cargo molecules have a long way to travel before they reach the synapse, and in oligodendrocytes, which require an immense increase in membrane surface in order to sheathe axons in myelin. Interestingly, in recent years, genes encoding Golgi-associated proteins with a role in membrane trafficking have been found to be defective in an increasing number of inherited disorders whose clinical manifestations include postnatal-onset microcephaly (POM), white matter defects and intellectual disability. Several of these genes encode RAB GTPases, RAB-effectors or RAB-regulating proteins, linking POM and intellectual disability to RAB-dependent Golgi trafficking pathways and suggesting that their regulation is critical to postnatal brain maturation and function. Here, we review the key roles of the Golgi apparatus in post-mitotic neurons and the oligodendrocytes that myelinate them, and provide an overview of these Golgi-associated POM-causing genes, their function in Golgi organization and trafficking and the likely mechanisms that may link dysfunctions in RAB-dependent regulatory pathways with POM.

Golgipathies in Neurodevelopment: A New View of Old Defects

“…COG6 mutations have also been associated with borderline POM in Shaheen syndrome (SHNS; MIM #615328) as well as a CDG with congenital microcephaly (MIM #614576) [82,83]. Interestingly, the COG complex has been shown to interact with molecules at all levels of GA organization and trafficking as well as a number of GA-associated RABs (see [4] for an overview). Table 2).…”

“…In terms of the physiological effects of mutations in these proteins versus mutations in proteins involved in trafficking per se, there might be a convergence, since the functional consequences of the lack of delivery of a modified protein to its target intracellular compartment and the lack of its modification in the first place are likely to be similar in at least some respects. In addition, the highly specialized nature of the nervous system implies a corresponding adaptation of GA trafficking function in the component cells (for example, the occurrence of Golgi outposts in dendrites), and correspondingly, defects in GA enzyme function often lead to neurological consequences (also reviewed in [2,4]). A prime example of this convergence is provided by the CDGs, which could be related to structural/mechanical deficits (e.g.…”

“…Indeed, the magnitude of this impact on the nervous system structure and physiology and on neurodevelopment in particular should not be surprising, when one considers the intensive use that neurons and glia presumably make of the GA -in the intricately coordinated processes involved in progenitor cell organization, orientation and mitosis; the subsequent highly directional migration of young neurons to their target regions; the exponential increase in surface area and thus of the biosynthesis of both membrane lipids and proteins required by diverse processes such as dendritic arborization in neurons and myelin sheath production in oligodendrocytes; the heavy demands of synaptogenesis and synaptic and neurosecretory activity, etc. The existence of Golgi outposts in dendrites is a prime example of the adaptation of the GA to the highly compartmentalized nature of the nervous system and its specific trafficking needs (reviewed in [3,4]).…”

“…Additionally, several of these newly or previously identified disorders appeared to involve a mutation in a GA-associated member of the small RAB GTPase family, which are involved in a plethora of trafficking functions in the cell, or in molecules that interact with the RABs, including their direct effectors and modulators such as the guanine nucleotide exchange factors -GEFs -which activate them by replacing GDP by GTP and allowing them to bind specific effectors, or the GTPase activating proteins -GAPs, which dissociate the active complex. These observations prompted us to propose the term "Golgipathies" or "Golgipathic microcephalies" to designate this emerging class of disorders characterized by a similar phenotype (POM, white matter deficits, notably an abnormal corpus callosum, and varying degrees of cognitive impairment), and caused by mutations in RAB GTPases or their molecular partners [4]. However, an examination of the literature and recently published studies provides ample evidence that defective GA proteins and processes are linked to a wide spectrum of neurodevelopmental defects in addition to the combination that first drew our attention.…”

A Neurodevelopmental Disorder Caused by Mutations in the VPS51 Subunit of the GARP and EARP Complexes

“…PCCA2 caused by mutations in VPS53 23 has been proposed to be part of a more general disease classification with shared pathophysiology, termed the 'Golgipathies' 36 . Golgipathies are inherited diseases that have a shared set of characteristics including microcephaly, white matter defects and intellectual disability.…”